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Full text of "Opening Statements Before the Committee on Appropriations"

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OPENING STATEMMTS 
BEFORE THE 
COMMITTEE ON AP^ROPRIAnONS 
1957 ESTIATE 
FOR THE 
NATIONAL INSTITUTES OF HEALTH 



NATIONAL INSnTUTES OF HEALTH 
PUBLIC HEALTH SERVICE 
U. S. DEPARH^^EWT OF HEALTH, EDUCATION, AND WELFARE 



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07C825 

OPENING STATMENT 

by 

Director, National Institutes of Health 

Public Health Service 

COMilTTEE ON APPROPRIATIONS 

1957 ESTIMTE 

for 

"Operating Expenses, National Institutes of Health" 

ViT. Chairman and I'.embers of the Committee: 

INTRODUCTIO N 

I appreciate this opportunity to lay before you our proposals for 
the budget of the National Institutes of Health for fiscal year 1957. 

This is my first appearance as Director of N.I.H. Dr. Sebrell, as 
you know, retired last fall. I have had the pleasure of presenting our 
direct operations to you in earlier years as Associate Director for Intra- 
mural Affairs. We have been most appreciative of the interest of the 
Committee in the total work of N.I.H., and in the Committee's support of 
our activities. 

The Director of N.I.H. has essentially two tasks in discussing 
the budget with legislative committees. The first is to place before the 
Committee the general picture of the total budget of N.I.H. - the major 
assumptions, major trends and major program developments. The second is 
to defend a segment of the budget - that part of the total N.I.H. budget 
covered by the appropriation called "Operating Expenses, National Institutes 
of Health." 

There is attached a statement (Attachment A) covering in some 
detail the specific activities which I wish to explain to the Committee. 

As background not only for these activities but also for the 
activities of each of the Institutes, I wish to place before the Committee 
some general principles applicable to the total N.I.H. activities. 



- 2 - 

DUAL N.I.H. FUNCTION— SUPPORT AND CONDUCT OF RESEARCH 

These activities fall into two broad groups. 

The first is support of medical research in the universities, 
medical schools and other nonprofit laboratories throughout the Nation. 
This encompasses not only the support of current research, but support 
of fellowships and other measures designed to train the medical investi- 
gators of the future. We also have a role, supporting the Bureau of 
State Services, in bringing the results of research to the point of 
application through technical assistance and grants to States for control 
of disease. In total, these so-called "extramural" activities account 
for about three-fourths of our total budget. They constitute such a 
substantial share of the total support of medical research in this 
country that our policies directly and significantly affect the course 
of medical research in this country. Our budget, and the program 
proposals reflected in the budget, embody the most important single set 
of decisions bearing upon American medical research. 

The second broad group of N.I.H. activities is the operation of 
the medical research laboratories, including the clinical research 
facilities, at Bethesda. At this point I shall confine my remarks on 
our own laboratories to the observation that the Congress is giving us 
the material things required to made the N.I.H. the most effective medical 
research center in the world. Our essential task is to use the funds and 
facilities placed at our disposal by the American people in a manner 
that will make them proud of their investment. 



- 3 - 
ORGANIZATION BY INSTITUTE 

The total job of N.I.H. is so large that it must be grouped and 
organized to be effective. As you know, the major guide to our 
administrative structure is organization around broad categories of 
disease. As you know, we have seven Institutes whose general function 
is an attack on groups of related diseases both through grants and the 
operation of laboratories at Bethesda. The Division of Biologies 
Standards and the Division of Research Grants comprise the remaining 
operating groups. The Office of the Director is responsible for general 
coordination of all activities and for certain research services that are 
most effectively provided by a single central organization, 

1957 BUDGET PROPOSAL IN BRIEF 

One of the first tasks that fell to me as Director was to work with 
Dr. Scheele and Secretary Folsom on the preparation of the 1957 budget. 
We thus had the opportunity to discuss the budget thoroughly with 
Mr, Folsom not only in terms of detailed needs and figures but in terms 
of the fundamental assumptions underlying the total budget. These 
discussions have led us to request very substantial increases for the 
coming year. The proposed budget totals $126.5 million, as compared with 
$99 million in fiscal year 1956. This increase of $27.5 million would 
provide an additional $24.. 5 million for the extramural programs, and $3 
million additional for our intramural prograriis, I have rounded off these 
figures to clarify the essentials of the budget. We appreciate this 
opportunity to explain what appears to us to be the logical basis for these 
proposals, dealing first with the grant programs and then with our own 
laboratories. 



- 4 - 

I should like to present the basic budgetary assumptions not only 
because they underlie our program proposals and the specifics of the 
budget figures, but also because they provide a general guide to the 
manner in which we hope to see the programs evolve. Each of the Institute 
Directors will indicate in more detail the proposed content and levels of 
their programs for the coming fiscal year, and highlight accomplishments 
during the current year. I should like to submit a statement for the 
record on these research highlights. 

Budget Assumption One — Current Aid. Manpower Training an d 
Facili ties , are In terrelated - I should like to present first our major 
guidelines for the support of research through grants to medical schools, 
universities and other nonprofit research centers. We think of support 
for medical research in terms of three fundamental things that are 
required. First; funds for support of current research are necessarily 
to pay salaries, to provide equipment and to purchase supplies. Second, 
well trained manpower must be available in adequate numbers because 
research rests essentially upon the ideas of individuals. Third, adequate 
physical facilities must be provided. One of the major problems in 
administering a research grant program is to reach sound judgments as to 
the relative need for support of each of these three interdependent 
elements. The three must be kept in balance, looking at both the 
immediate future and the long run, if research is to be fully productive. 
We undertake to frame our budgetary proposals so that funds provided by 
N.I.H., considered as a supplement to private support, contribute to a 
balanced situation. 



- 5 - 

Assumption Two—Planned Progress Towards Full Use of Capabilities 
Is Wise - Consider first the support of current research through research 
grants. A broad assumption underlying the N.I.H. research grant budgetary- 
proposals is that it is in the National interest to move in a planned 
manner towards utilization of the full existing medical research capacity 
of the Nation through support from private and governmental sources. 

A major policy question is the rate at which the goal of full 
utilization of existing capacity should be approached. Overly rapid 
extension of research support is unwise because of the adverse effect 
upon the average quality of research supported, and because funds may 
be committed for substantial periods to immaturely considered lines of 
activity. On the other hand, extension of support at too slow a rate 
leaves work of high quality by highly competent investigators unsupported 
or inadequately supported. 

In our judgment the proposed research grant budget is set at a 
level which avoids both of these dangers. We propose an increase of $18 
million in research grants. 

Assumption Three — Research Needs Exceed Current Rese arch 
Capabilities - In this connection, I wish to draw a clear distinction 
between the volume of funds which would have to be expended to capitalize 
fully upon what one may call research opportunities in each separate disease 
field, and a total budget which takes into account our total National 
capacities in terms of manpower and facilities. The needs for research 
funds in separate disease fields, considered as funds that could be 
effectively expended if each research field had an exclusive claim to 
available resources, naturally exceed the amounts that can be expended when 
all disease fields are considered together. 



- 6 - 

To take a specific example of competing demands, the effectiveness 
of programs for screening drugs effective in relieving high blood pressure 
and for screening drugs which cause tumors to regress both depend heavily 
upon the availability of scientists specifically trained to evaluate the 
effects of drugs — pharmacologists. Highly trained pharmacologists are in 
short supply, and this shortage is one factor affecting the size of both 
programs. Those who view medical research primarily as heart research or 
cancer research or research in any other single category are not required 
to deal with the total picture. As responsible administrators we must 
look at all fields and undertake to strike a balance. Accordingly, the 
proposed budget takes into account the problem allocating limited resources 
among competing fields. 

Assumption Four — Increased Support for Basic Medical Research I s 
Neede d - VJe see the problem of designing the research grants programs so 
as to increase the productivity of research as being critically important. 
One of our most difficult and most important tasks is to administer the 
funds appropriated by Congress in a way that will return the most to the 
taxpayer in terms of findings applicable to the control of disease over 
the long run as well as in the immediate future. VJe have a strong 
conviction, shared virtually unanimously by the entire medical research 
community of the Nation, that increasing attention should be paid to the 
areas of medical research fundamental to all diseases. This has been our 
policy in the past. For example, Dr. Sebrell said in testifying before 
this Committee on the N.I.H. budget for fiscal year 1955, "We plan to 
continue support, not only to clinical investigations and research directly 
applicable to medicine, but also to studies which are relevant to under- 
lying problems but not immediately applicable to medicine. We consider 



- 7 - 
this approach to be so important that — in addition to giving it. support 
from the programs of the various Institutes — we have a program directed 
especially to support of basic studies which are related to medicine as 
a whole instead of to single disease categories." Our budget for fiscal 
year 1957 contemplates an increase of $3 million for such general grants 
not administered by any of the Institutes. 

In addition, the research grants programs of the Institutes have 
been operated in a manner ensuring that scientists interested in the 
fundamentals of disease processes are given a broad charter to explore 
at the boundaries of knowledge. We consider this study of fundamental 
problems within the disease categories to be a critically important 
matter, and propose to continue this policy. 

Assumption Five — Planned Exploitation of Leads Is Froductive - A 
quite different approach is necessary to complement these vital areas of 
investigation where the investigator must not be coBimitted in advance 
toward a clearly defined goal. We are convinced that when the full 
scientific or medical significance of a research finding can be proved 
out by the voluntary collaboration of a large number of investigators 
drawn together in a planned National effort, such research should be under- 
taken. In our opinion, the ability to mount such large scale research 
efforts is a major post-war development in American medicinej and one 
which would have been impossible without substantial Federal aid. The 
technique has proved itself in such investigations as penicillin therapy 
for syphilis, streptomycin treatment of tuberculosis and exploration of 
the full effects of cortisone. 



- 8 - 
These large scale collaborative efforts are most emphatically not 
a substitute for the exploratory work of individuals, but they have a 
real role in specific circumstances. The most important of these 
circumstances is the existence of findings that warrant thorough 
exploration. This is the case with chemotherapy of cancer, a program 
which Dr. Heller, Director of the National Cancer Institute, will 
describe in detail. Dr. Bailey, Director of the National Institute of 
Neurological Diseases and Blindness, will also, lay before the Committee 
his plans for an extensive integrated research program in cerebral 

palsy^ patterned in general terms along the lines of the dramatically ' 

« 

successful effort on retrolental fibroplasia. . 

Even before a key finding appears, a relatively sterile but 
important field may be energized by the attraction of investigators with 
fresh and diverse viewpoints. The extraordinary development of research 
in the fields of arthritis and metabolic diseases over the past few years 
is a clear example of the manner in which leadership and funds can lift 
the level of research in terms of both volume and quality. Dr. Daft, 
Director of the National Institute of Arthritis and Metabolic Diseases, 
will summarize thig most interesting development. The existence of these 
gap areas plays a part in determining how the total budget is distributed 
by fields. 

We are proposing increases in research grants ranging from $4- 
million for the National Cancer Institute to $379,000 for the National 
Institute of Dental Research. These increases among Institutes have 
been designed to bring us towards the general objective of better balance 
among Institute programs. 



- 9 - 

I turn now from the first of the three basic elements of research 
support, aid for current research, to the second element, training of 
research manpower. 

Assumption Six — The Medical Re s earch Manpower Pool Should Expand - 
We plan on the assumption that more and better trained medical investigators 
will be needed if the total medical research program of the Nation is to 
expand in scale with the total economy. We believe, however, that manpower 
training programs should not be indiscriminate, but designed to accomplish 
certain specific objectives. These objectives are to (l) attract potentially- 
competent investigators to careers in medical research, (2) establish wider 
opportunities for stable careers in medical research as a means of retaining 
trained manpower, (3) increase the quality of training, {U) direct special 
efforts towards those areas where relative quantitative and qualitative 
deficiencies are most significant as measured by the developing needs of 
medical research, and (5) train manpower for medical care and community 
service in selected areas where there are severe absolute shortages as in 
the case of care of the mentally ill. 

The manpower training proposals in the 1957 budget are framed in 
accordance with these assumptions. 

We propose that the 1956 budget for research fellowships and training 
grants, totalling $17.3 million, be increased by $3.7 million to a level 
of |21 million in fiscal year 1957. With this $3.7 million increase we 
can accomplish two things of general significance to the future of American 
medical research. First, we can help train additional people in disease 
areas where the outlook for an adequate supply of manpower in the future is 
distinctly unfavorable. These are arthritis and metabolic diseases, 



- 10 - 
neurological diseases and blindness, mental health, heart disease and 
dental disorders. Second, we can increase research activities in the 
sciences basic to medicine by providing support on a stable basis to 
carefully selected investigators so as to augment the numbers of scientists 
in these areas of fundamental concern. It is a matter of considerable 
alarm to note that there is a serious and increasing shortage of research 
and teaching personnel in many of these so-called preclinical sciences 
fields. I believe it is of the utmost importance that the attack on the 
more fundamental aspects of disease be supported not only by funds for 
current research but also by taking steps now to provide for the future. 

Assumption Seven — More Adequate Research Facilities Are Needed - The 
third element of a total program for support of medical research is 
provision of adequate facilities. Although the proposed budget for N.I.H. 
does not contain funds for such a program, there is no doubt but that 
improved and enlarged medical research facilities are badly needed. 
Moreover, it is clear that only Federal action will supply the funds 
required for a far-sighted medical research facilities program. Accordingly, 
grants for research facilities construction were proposed in the President's 
State of the Union Message. Enactment of legislation, followed by an 
adequate appropriation, will provide the third element of a comprehensive 
and balanced program of support for medical research. 

A well rounded research support program that provides for the 
future through manpower training and facilities construction as well as 
for the present through current support of investigations in progress will 
assure the Nation of a growing stream of research findings. Such a program 
is in sight. 



- 11 - 

Assumption Eight — R esearch to Ensure Application of Basic Findings 
Is Need ed - But research findings do not translate themselves into practical 
measures for disease control. For this reason, our budget provides funds 
to States for disease control, and also for professional and technical 
assistance to States on control of disease. 

Our major assumption for budgetary planning in this area is that 
grants for control of disease and for professional and technical assistance 
administered by N.I.H. should expand only in response to specific findings 
that may through further research and development offer promise of 
substantial advances in control of disease. In conformity with this 
objective, only one substantial increase is proposed in this area, namely 
for extension of the cytological test for early detection of cervical cancer. 

Assumption Nine — Full Use of Facilities at N.I.H. Is Desirable - I 
turn now to the direct operation of the N.I.H. It is our hope that progress 
toward full utilization of the Clinical Center and related buildings will 
continue. The proposed budget provides for this. 

With virtually full utilization of the new facilities at the N.I.H. 
by the end of fiscal year 1957, we do not see at this time any major new 
expansion of the direct research operation at N.I.H, 

From time to time, however, certain specific unforeseen problems 
may generate budgetary needs for the direct operation. We have an example 
of such a need in the budget proposed for fiscal year 1957. In our opinion, 
the function of assuring the public that biologies products (including 
all types of vaccines) are pure and effective should be more adequately 
financed. The fundamental reason for this opinion is the growing number 
and complexity of biologic products. The more successful medical research 



- 12 - 
is, the more rapidly do usable biologic products become available. If we 
have a sound and adequately financed biologies control operation, the 
time between laboratory findings and widespread application of the 
findings in the form of safe and pure biologies can be substantially 
reduced. 

We have taken steps to ensure that the additional funds will be 
expended most effectively. These steps include establishment of mechanics 
for securing more comprehensive information from the regulated industry, 
reorganization of the regulatory activity and initiation of a research 
program carefully designed to support the regulatory function. 

Conclusion — Sustained Growth of Medical Research Is in the National 
Interest - Now, having sketched for you quite briefly our objectives for 
the year ahead, I wish to emphasize that we see the 1957 budget not in 
isolation, but a logical development from past events and as a logical 
step towards the evolution of the program over the next decade. Our long 
range plans rest upon the assumption of continuing growth of the economy, 
continuing expansion of research and development as a prerequisite to 
economic growth, and continuing expansion of medical research as part of 
the Nation's total research and development program. Therefore — and this 
is a point of particular importance — we look upon the problem of financing 
medical research not as one of assessing when medical research will reach 
a plateau set by the availability of manpower and facilities, but as one 
of devising means of securing as a Nation an expansion of productive 
medical research as the total economy grows. Over the next decade, these 
means will most certainly include the simultaneous growth of Federal, State 
and private support which has been such a prominent characteristic of the 
ten years that have just elapsed. 



- 13 - 
Finally, let me express a personal conviction that medical research 
is not ultimately justified on economic grounds, spectacular as the direct 
monetary gains from medical research have been and will be. The essential 
justification for medical research, which needs no support from profit and 
loss calculations, is that it reduces human suffering and extends human 
life. 



ATTACHI4ENT A 
TO 
OPENING STATEMENT 
by 
Director, National Institutes of Health 
Public Health Service 

COMMITTEE ON APHIOPRIATIONS 
1957 ESTIMATE 
for 
"Operating Expenses, National Institutes of Health" 

The item "Operating Expenses, N»I.H." covers three quite distinct 
activities. The first is the research grants and manpower training 
activities of the Division of Research Grants, The second is a set of 
auxiliary research services and clinical services that are operated 
centrally for reasons of economy and efficiency. The third is the 
operations of the Division of Biologic Standards, The three activities, 
will be presented in that order, 

DIVISION OF RESE AH CH GRANTS 

I should like to present first the general research grant and 
fellowship program of the Division of Research Grants, 

We have always defined broadly the lines of research pertinent 
to study of specific lines of disease. Hence, a substantial volume of 
research basic to clinical medicine has always been supported by 
appropriations to the Institutes, and we intend to continue this aid. 

However, there remains a substantial and significant volume of 
basic medical research that can not be encompassed by the Institute 
programs. The unprecedented advances in the conquest of disease since 
World War II are beginning to overreach the fundamental knowledge that 
we have amassed over the years. Without the replenishment of such 
basic resources, we are faced with the prospect of progressively 
diminishing returns in clinical and applied medical research in the 
future. Support of research of this kind is the first function of the 



I. ■'!■ 



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'[iO-,: !.;v. 



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grant program of the Division of Research Grants. These fundamental 
studies will be expanded, including work in biochemistry, with emphasis 
in the field of histochemistry; biophysics, general physiology, including 
normal and abnormal processes of growth, metabolism and aging. 

This area of research is typified by studies on the structure 
and function of cells. At the basic level of the single biological 
cell, the progress made in determining the cellular contents such as 
ribonucleoproteins has shown that the key to hereditary factors, 
multiplication, and growth may be found in these materials. Such 
accomplishment as the recently found method for obtaining these 
substances in a less degraded form emphasizes the need for further 
effort in this basic approach to the problems of human existence. 

In addition to the research basic to all diseases, many important 
problems relating to medicine that are important but not necessarily 
fundamental in a scientific sense fall outside the seven categorical 
programs of the Institutes r For example, medical research is 
increasingly dependent upon precise measurements of physical phenomena. 
These measurements are made by instruments that produce incredibly 
exact data, often on microscopic quantities of material. Further 
advances in medicine depend heavily upon continuing advances in 
instrumentation, but the research required for these advances does 
not lie in the province of any Institute, 

Another problem area that does not fit into the program of 
any Institute relates to environmental poisons. The rapid increase 
in the number of chemical compounds to which people are exposed raises 
the question as to what effect the daily contact with these products 
may produce, not only as direcL toxica- .ts to man but also more 



■■(;.:■•; ■-':':' \ 



- 3 - 

indirectly through their actions upon the organisms associated with 
man in health and disease. 

Our dependence upon chemistry is typified not only by unprece- 
dented use of poisonous pesticides, synthetic fibers, and plastics, 
but also by recent developments in the widespread use of antibiotics 
for the control of animal and plant dieeases. 

These problems must be approached from several angles. One of 
the most important is to define precisely what the processes of poisoning 
are— what body systems are affected, how they are affected, and how the 
body protects itself against poisons. This is fundamental toxicology. 

Research of a more applied nature is also required. 

Dermatological research is necessary if we are to understand more 
fully how the human skin protects against poisons, the conditions under 
which this protection fails, and the consequences of failure. Recent 
advances made in understanding the glandular and enzyme mechanisms of 
the skin point out the essential need for continued support in this 
field. Support of research areas such as this is the second primary 
function of the grant program of the Division of Research Grants. 

The third major function of the Division is to administer 
programs for the training of research manpower not for any clinical 
specialty but for basic research. Four of these programs deserve 
special mention. 

ESTABLISHi^MT GF A SENIOR RESEARCH FELLCMSHIP PROGRA/'I 

As is true of all research, medical research is essentially the 
product of intelligent, highly trained minds. Hence an essential part 
of a well rounded Federal program for support of medical research con- 
sists of carefully designed programs for the training of manpower. 



, V iiVA-i.-ir:^' 



- 4 - 
Just as the sciences basic to medicine are critically important to 
the advances of the futureji the training of scientists to work in 
this area is a matter of high priority. Unfortunately, the sciences 
basic to medicine are not as strong as they should be in the medical 
schools. Research careers in these fields, which include such fvinda- 
mentals as biochemistry, pharmacology, physiology, microbiology and 
pathology, are not particularly attractive in the medical schools. 
Many of the most able investigators in these fields are attached 
to clinical research teams. They are valuable in this capacity, but 
their most distinctive contribution — fundamental work in their field 
of professional competence — suffers. Since these fields are relatively 
unattractive, teaching as v/ell as research suffers, and there is a 
distinct danger that talent of high caliber will not be attracted in 
adequate volume to the sciences basic to clinical medicine. 

These observations derive from careful inquiries which we have 
made over the past two years. They have led us to the conclusion that 
a new program designed specifically to deal with this problem can make 
a critically important contribution to the productivity of the medical 
research effort of the entire Illation, Conversely, failure to adopt such 
a program will permit a situation which is now urgent to develop into a 
serious threat to medical research. 

To deal with the problem we propose to provide stable support for 
a minimum of five years at an intermediate salary level for outstanding 
young investigators in the preclinical sciences. These scientists will 
have secured their Ph.D, degrees, and many of them will also have secured 
the M.D, degree o They will have had a few years post-doctorate experience. 
For this reason, the support will be called Senior Research Fellowships. 



- 5 - 

They tjxII be noitiinated by their institutions, and selections will be 

made centrally x-dth ihe aid of scientific ad^/isory bodies. The assured 

support for at least 5 years is designed to provide career stability at 

the time when investigators in the sciences basic to medicine typically 

find great difficulty in finding posts \-ihere continuity of support is 

certain. IJith reasonable salaries will go a modest research grant for 

work of the senior fellow's choice. In addition he will be permitted to 

teach to the extent required to make hira eligible for a tenure academic 

post, and hence to increase the probability that he will spend a full 

career in research. 

Our plan is to add to these funds fey comparable increments each 

year for five years. Stipends and supporting research funds will allow 

increments of lj.0-50 senior research fellowships per year, trained to 

the level of associate professor or professor, 

ESTABLISHia^IT OF TRAIIIING GRANTS IN Sr.LECTED SCHCOLS OF IiEDICII'lE, 
DSIvTTISTRI Am PUBLIC h:'j\lth 

Increasing numbers of medical research personnel must come from 
the professional schools, yet these workers as students receive a medical 
training experience primarily designed to produce practicing physicians, 
dentists, and public health workers. Unlike the university-trainedJPh^DT' 
candidate, these individuals have had little or no training in research 
methodology, procedure, and theory, and so they are handicapped in 
proceeding effectively to advanced research training. 

There is an urgent need to augment training in the fundamentals 
of research methods mthin the medical school environment as a primary 
objective. This must, however, be done in a way that fits the research 
training of selected individuals sm.oothly into an already crowded 



- 6 - 
experience. For this reason, careful experimentation tjith alternative 
plans xri.ll be required before the problem can be solved. Since funds 
have not been forthcoming from other sources for such a program^ grants 
for training in research methods are proposed. 

It is proposed to make grants in fiscal year 19^7 to about five 
schools in the amount of 0100,000 apiece. Tliis grant is to be expended 
over a 5-year period, mth the year-by-year breakdown to be determined 
by the recipient institutiono 

In subsequent years, additional medical schools which demonstrate 
willingness and competence to deal with the problem will be offered 
similar grants, with the total annual appropriation request for this 
program not to exceed 0500,000. 

EXPMSION OF THE PART-TIME ICDICAL RESEARCH FELLOUSHIPS 
This program, operated in 1955 arid 1956 as a pilot study, has 
proved to be a most realistic approach to the problem of interesting 
the young professional school student in research at an opportune.^±im©,— 
It is now planned to provide up to 8 units for each medical school, A 
unit consists of OUOO plus l5/S indirect costs, with the selection of 
fellows and their utilization in research being the responsibility of 
each school, 

RESEARCH IH ITORSING 
A fourth special program relating to manpower resources is 
designed to relieve the shortage of nurses. There is little prospect 
of overcoming this shortage exclusively through training of additional 
nurses. It is therefore necessary to develop ways to utilize nurses 



11 



- 7 - 
more effectively — in short, to find how each nurse can care for more 
patients. 

This is a research problem of great complexity. It has many of 
the aspects of manpower utilization studies in industry. Time and 
motion studies, studies of skills required on the job, isolation of 
tasks requiring higher and lower skills, motivation and space layout 
must all be investigated. These investigations are required in 
hospitals, in an environment and under conditions where sound research 
is difficult and expensive. But the potential returns, in terms of 
expanding the effective supply of nurses, are high. 

In recognition of this problem, $625,000 was earmarked in 1956 
appropriations to support research and training in nursing services of 
which $500,000 was designated for support of research grants and $125,000 
to support research fellowships in this field. Identical amounts are 
proposed for 1957. Grant and fellowship applications are being received 
and processed at the present time at a rate to ensure effective utiliza- 
tion of 1956 funds. During 1957 it will be possible to evaluate fvirther 
the needs of this very important program, 

SUWyVjARY 

The funds proposed for training of manpower in areas of particular 
need, combined with more extensive support of basic research and other 
important investigations that do not fit into the seven categorical 
programs, will serve to strengthen and round out the current medical 
research of the Nation, and to expand our National research capability 
in the future. 



I 



- 8 - 

AUXILIARY CLINICAL AMD RESEAR C H SERVICES 
The second major set of activities financed under "Operating 
Expenses, N.I.H." is the auxiliary research and technical services 
discussed in the budget before you under the heading of "Reimbursable 
Obligations." These services constitute an essential component of 
N.I.H. intramural research. Their primary mission is to provide for 
the research operation the highest possible degree of service 
efficiency and technical know-how. These services are carried on 
centrally because they represent needs comm.on to all Institutes and 
because they can be provided most efficiently and economically from a 
central point. They include a complete range of both clinical and 
laboratory services as well as the usual administrative and housekeep- 
ing services. Since these services are costs of research, they are 
financed from each Institute's appropriation. For administrative 
simplicity and operating effectiveness, the funds are pooled in one 
N.I.H. appropriation account. 

THE CLINICAL CENTE R 
The newest and largest of the centralized service facilities is, 
of course, the Clinical Center. The services provided by the Clinical 
Center range from highly specialized nursing to housekeeping. As you 
know, this facility is designed, both as to structure and organization, 
to facilitate the integration of laboratory and clinical research. The 
Institute Directors will indicate, by examples, how this integration 
contributes to research, A full description of the research is impossible 
because more than 100 clinical investigations are in progress. 



- 9 - 
The proposed budget provides for continued progress toward full 
utilization of the Center and related auxiliary service facilities. 
We expect to have 4-50 clinical research beds opened by the end of fiscal 
year 1956, as compared with 373 at the beginning of the year. The major 
service increases in 1957 are to carry the 1956 level of 450 beds for a 
full year and in addition to move toward complete activation of the 
total 510 bed complement by June 30, 1957. Within the funds available 
in this budget, we will make every effort to reach this objective 
recognizing, of course, that the numbers of activated beds which can 
be occupied by research patients depend upon two limiting factors: 

1. Our ability to recruit and train the necessary additional 
patient-care personnel, especially nurses, and 

2. The medical requirements for patient services which are 
determined by the research character of the patients admitted for 
study during the budget period » 

The total Clinical Center operation is proceeding satisfactorily, 
although we face some real problems. There are now active research 
psrograms in 20 of the 23 available nursing imitsj the remaining 3 will 
be activated by the end of the next fiscal year. 

We have had little difficulty in securing qualified patients. 
Patients are returning for research follow-up after discharge. Currently, 
about 1,500 follow-up visits per month are madeo 

We are gradually building in the full planned array of research 
and patient care services ^ A comprehensive rehabilitation service is 
now available, and we now have a full-time resident chaplain. 

The program for training specialized clinical associates — our 
research analogue of the more general residency training offered in 



- 10 - 
hospitals — is proceeding wellt Six programs have been approved by 
the appropriate American Specialty Board, and the Clinical Center 
as a whole has been accredited by the Joint Committee on Hospital 
Accreditation. 

Our most difficult problem is in recruiting and retaining 
nurses. We face the general shortage affecting all medical care 
institutions. In addition, we face some difficulties peculiar to our 
operation. The v/ork is exacting, and many of the research patients 
are difficult to take care of. We believe, however, that ways to 
relieve the shortage can be worked out. 

DIVISION OF BIOLOGICS STAM3ARDS 

The second major program area covered under this appropriation 
is the biologies standards program, including the polio vaccine opera- 
tion. You may recall that, in June of this year, authority was granted 
the Surgeon General by the Secretary of the Department of Health, 
Education, and Welfare to expand the biologies fujiction of the Public 
Health Service with the status of a separate division within the 
National Institutes of Health, to be called the Division of Biologies 
Standards. 

This step was taken as the culmination of developments in 
medical research related to: (l) the expanding range of diseases to 
which biological products may be applicable, (2) the kinds of new 
biologieals which may be available, particiolarly in the field of 
virology, and (3) the greatly shortened time interval between the 
discovery of new biologieals and their use, as was evidenced this 
spring in the rapid initiation of the poliomyelitis vaccine program. 



- 11 - 

As a separate entity, the nev Division has both a clearer 
mandate and a better opportunity to conduct such research as is 
essential to deal with trends, advances, and problems in biologicals. 

The provisions of the Public Health Service Act require that 
all products falling under the term "biological products" be licensed 
to ensure their safety, purity, and potency. This includes both 
licensing of the manufacturing establishment and of the individual 
products. To fulfill these provisions, staff members of the Division 
inspect manufacturing establishments, perform tests in their own 
laboratories, examine manufacturers' records of processing and testing 
(protocols), and confer with appropriate representatives of industry 
and with scientists in the field. Members of the staff also engage in 
research to improve existing biological products, to develop new ones, 
and, particularly, to provide the soundest possible scientific base 
for the regulatory activity, 

THE POLIOMYELITIS PROGRAM 

Events of the past year have emphasized the importance of 
biologies control and its role in future developments of preventive 
and therapeutic medicine. The discovery of a process whereby polio- 
myelitis virus could be killed by a chemical agent without destroying 
antigenicity was followed in rapid succession by a field trial con- 
ducted by the National Foundation for Infantile Paralysis, formulation 
of [lAinimum Requirements for the manufacture of the vaccine, licensing 
of manufacturers to produce this material, and initiation of a program 
to vaccinate all children between the ages of 5 and 9 years. 



- 12 - 

The potentials of research for gaining the objectives of 
satisfactory control have been clearly demonstrated within the past 
six months. During this time the activities of the Division have 
been intimately concerned with problems related to the development and 
production of poliomyelitis vaccine. The occurrence in late April 
of cases of paralytic poliomyelitis associated with inoculations of 
vaccine sharply emphasized the need for an enlarged control group 
capable not only of carrying on the fvmctions of control, testing, 
and developmental research, but also of engaging in basic research 
in fields directly related to problems arising in the attempt to 
control both new and old biological materials. Without a significant 
basic and developmental research program it is not possible to operate 
an effective control program. 

There is every evidence that with rapid scientific advances the 
testing program for poliomyelitis vaccine, as well as for other 
biological materials, will be progressively changed in order to further 
ensure safety, pvirity, and potency. 

A cogent illustration of the indispensable link between research 
and the control activity is provided by recent changes in the method 
of testing poliomyelitis vaccine for safety. An intensive research 
program was undertaken in the spring of 1955 by manufacturers, members 
of the Technical Committee for Poliomyelitis Vaccine, and scientists 
in this Division and other laboratories in an effort to increase the 
sensitivity of the monkey safety test. They found that the simultaneous 
injection of cortisone intramuscularly with an intraspinal injection of 
vaccine considerably increased the monkey's sensitivity to poliomyelitis 
infection. While the monkey safety test previously employed was less 



- 13 - 
sensitive than the tissue culture tests prescribed in the Minimum 
Requirements established for producing and testing the vaccine, the 
new monkey test is more sensitive. This modified monkey test has 
detected living virus in all vaccines suspected or demonstrated to 
have produced poliomyelitis in the field, although the tissue culture 
test used failed to detect living virus. 

During the past several months, vaccine manufacturers have 
progressively instituted the nev; test, and on November 11 it i^ras 
incorporated into the Minimum Requirements in its present form. 
This means that vaccine lots can now be cleared v/ith a greater degree 
of assurance than was possible under the original testing procedures. 

To take another example of the tight bond between research and 
a sound control operation, recent study of the fundamentals of tissue 
culture testing has indicated that a greater measure of safety is 
assured by testing 1,500 ml. of each lot of vaccine in the Division 
instead of the 10 ml. sample previously tested. Five tissue culture 
teams are required to examine vaccines by this method. 

Finally, intensive research has indicated the necessity for 
removal from the vaccine of particles within vrhich virus may be 
protected from inactivation by formaldehyde. Provisions have been 
made to ensure the removal of such protected particles by suitably 
spaced filtration procedures. 

Much has been done about poliomyelitis — over 27 million mis. 
have been released since July 1, but the situation is by no means 
stabilized. Although a large group of school-age children received 
complete vaccination in 1954- and a very much larger group received 



- u - 

some vaccine in 1955? the present program must be regarded as an early 
step toward the prevention of the disease. There will undoubtedly be 
additional technical refinement of the vaccine. New vaccines produced 
by different methods are a possibility. But we can surely look with 
confidence toward a time when paralytic poliomyelitis will, like 
smallpox and typhoid, join the vanished plagues of a by-gone era, 

OTHER E.VERGING PROBLEi.lS 

Recognition of the increasing significance of biologies control, 
not only in terms of poliomyelitis vaccine but also in terms of the 
total field of biological products generally, has necessitated an 
expanded program for the new Division, The scope of its biologies 
control function must permit active participation in all facets of 
research concerning biological materials. With responsibility for 
quality and safety control of all biological products, the Division 
must be strengthened to keep abreast of the rapid development in this 
field, particularly in the area of virus vaccines. 

Research activity in hepatitis, which is a serious problem in 
the use of blood and blood products, will also be expanded. One form, 
infectious hepatitis, is one of the most prevalent virus diseases in 
the United States and one which may have severe after effects. Exten- 
sive efforts are being made to cultivate the responsible agent. As 
soon as this is accomplished, studies will unquestionably be directed 
toward development of a vaccine. 

Research should also be initiated in the area of prophylaxis of 
certain viral respiratory diseases, and in the area of prevention of 
measles by specific vaccines. 



- 15 - 

In addition to current research on such problems as pertussis, 
diphtheria, and shigellosis, control of biologic products which may- 
be employed in the treatment and prevention of allergies is essential. 
It is planned that the Division will study methods to extract allergens, 
evaluate their effectiveness, and conduct other research related to the 
control function. 

The idea that at least some classes of animal tumors are caused 
by viruses is supported by a steadily increasing body of data. Addi- 
tiAoal research on the production of antiserums directed against various 
tumors, without respect to the primary etif^logical agents,- is being 
vigorously pushed in a number of laboratories.- In both categories of 
research there exists the inherent possibility that some therapeutic 
product for human use will result. The Division would, in all likeli- 
hood, be directly involved in the problems of issuing licenses and 
of devising adequate tests for safety, potency, and purity. It is 
planned to set up a relatively small research unit to provide the 
Director with a continuous assessment of the possibilities in this 
field. Such a unit would serve as the nucleus of any expanded program 
which might become necessary if effective therapeutic products in this 
field do become available. 

The assurance of effective control measures can be provided 
only if the Division's own laboratories are fully prepared to handle 
emerging problems through conduct of a continuous research program, 
SIGNIFICMCE OF RESEARCH RELATED TO CONTROL OF BIOLOGICS 

The essence of a sound biologies control program lies in a 
sound research program, directed by a wide knowledge of the entire 



- 16 - 
field of medicine as related to the use of biological materials. An 
adequately supported program based on this awareness will enable the 
Division to gather essential experimental data before, rather than 
after, the problems are placed before us. The confidence with which 
procedures are accepted and employed would be greatly increased if 
data presented could be compared to that gathered by the Division's 
staff; then, if discrepancies should appear, further investigation 
could be made. The recent difficulties associated with poliomyelitis 
vaccine might have been avoided had evidence existed in this Division 
which would have either supported or rejected the claims of other 
investigators. It is inconceivable that the Public Health Service 
should be placed in a similar position regarding future biological 
products when the expenditure of relatively small sums will permit 
laboratory findings to be applied rapidly in large scale production 
with full assurance of safety. 

The budget estimate for the Division now under consideration 
represents one major step in the direction of creating a sound 
biologies control program. 



OPENING STATEMENT 
by 
Director, National Institute of Arthritis and Metabolic Diseases 

Public Health Service 

COMMITTEE ON APHIOPRIATIONS 
1957 ESTIMATE 
for 
"Arthritis and Ifetabolic Disease Activities, Public Health Service n 

Mr. Chairman, Members of the Coiranittee: 

HISTORICAL BACKGROUITO 

The National Institute of Arthritis and Metabolic Diseases was 
established in 1950 under the provisions of Public Law 692, incorporating 
several well-known and productive laboratories in basic science of the 
previously existing Experimental Biology and Medicine Institute, Under this 
reorganization, new areas of research directed specifically against the 
rheumatic and metabolic diseases, including rheumatoid arthritis and diabetes, 
were added. 

The first appropriation to support the new activities of the Institute 
was in 1952, when a total appropriation of approximately h million dollars was 
made available. This support has been increased in successive years, reaching 
approximately 7 million dollars in 1951^, 8 million dollars in 1955, and 
11 million dollars in 1956. 

There has been an extremely rapid growth of public and professional 
interest in the fields of responsibility of this Institute, In 19hS, less 
than $U5,000 was spent on rheumatic disease research; this year, from 
government and private sources, it is estimated that approximately 3 million 
dollars is available for rheumatic disease research and training. In the 
field of diabetes, the National Institutes of Health expended less than 
$50,000 in 19 51 J this year, the figure has grown to an estimated $1,500,000, 
This increase in interest and support has been acconpanied by major advances 
in knowledge, both in the area of basic metabolic reseaiMh and in our under- 
standing of such diseases as arthritis and diabetes. 



Some diseases seldom cause death but, instead, make life almost unbearable. 
Such a disease is rheumatoid arthritis. 

Other diseases not only kill but also progressively weaken and predispose 
their victims to early death from other causes or complications. Such a disease 
is diabetes. 

These are representative members of the two large families of diseases 
which claim the attention of the National Institute of Arthritis and Metabolic 
Diseases, 

The rheui-iatig diseases 

The first of these families is the rheumatic diseases. This family of 
diseases may conveniently bo divided into three major groups, depending on the 
tissues involved: those affecting the intrinsic structures of the joint (the 
various types of arthritis); those involving the accessory joint structures, 
such as tendons, ligaments, bursae, and muscles (non-articular rheumatism); and 
finally, those affecting the connective tissue framework of the body (collagen 
diseases). The first, or arthritis group, is characterized by pain and stiffness 
in the joints and muscles, often resulting in swelling and inflammation of the 
joints. Rheumatoid arthritis is perhaps the most important and certainly the 
most vicious typo in this group. Other forms of arthritis are osteoarthritis 
(associated with aging), gout, tuberculous arthritis and rheumatic fever. In 
the second group, no.&-articular rheumatism, may be included fibrositis, bursitis, 
neuralgia, lumbago, sciatica, and neuritis. In the third group, the collagen 
diseases are disorders whose names are almost as difficult as the medical 
problems they present — systemic lupus erythematosus, scleroderma, 
polyarteritis nodosa, and derma toiryositis, 

METABOLIC DISEASES 

Perhaps even more extensive than the rheumatic diseases is the second 



- 3 - 

metabolic diseases, of which diabetes is an important member. Some of these 
diseases have claimed the attention of physicians since the early days of medicine j 
many, however, are being recognized only today and as yet are imperfectly described 
and poorly understood. 

Metabolism is the complicated biochemical process by xi/hich the body converts 
food, air and viator into energy and growthj it is the basic life process by -which 
the body maintains its structure and function. Hormones, cnzymios and vitamins 
control various phases of this process. Metabolic diseases occur when something 
goes wrong in the complex maze of the body's metabolic machinery,,,, a hormone is 
prevented from doing its important jobj a vitamin is lacking, or an enzyme fails 
to function as it should. 

Patients with diabetes mcllitus or "sugar diabetes" cannot metabolize 
sugar properly because insulin, a hormone secreted by the pancreas, is lacking 
or does not function properly. Uncontrolled diabetes may progress rapidly to 
diabetic coma or fatal acidosis, liany patients develop secondary complications, 
such as coronary thrombosis, disabling nerve lesions, arteriosclerotic 
degenerative diseases, kidney disease, gangrene of the extremities or blindness. 
The disease is moat frequently found in persons over forty years of age, in 
those who are overweight, or in those who have a history of diabetes in the 
ftmily. Mild diabctos riay not produce symptoms recognizable to the patient and 
may be present for some time before it is discovered. The disease is most serious 
when the diabetic does not know of his condition or when, oven though knowing, 
ho allows the condition to got out of control. 

Other metabolic diseases resulting from errors or defects in metabolism 
are cirrhosis of the liver, certain types of anemia, and osteoporosis. Included 
also are a number of diseases of children, such as one in which the child is imable 
to metabolize milk sugar (galactosemia); and another, in which the child may 



starve while eating normally because of failure to digest food (pancreatic 
fibrotic disease), 

JJef iciencics in the diet cause other tyjocs of me tabolic diseases, such as 
the vitamin deficiency disorders ^ beriberi and pellagra, or the mineral 
deficiency diseases such as secondary anemia and goiter. Other deficiency 
diseases include sprue^, pernicious anemia, and the megaloblastic anemias of 
infancy and pregnancy. Diet also plays an important part in the prevention 
and treatment of diseases such as peptic ulcer. 

Another condition which should be classed as a metabolic disease is 
obesity. This disorder is more significant as a health prc>'lcm than many people 
realize because it predisposes its victims to such serious diseases as diabetes, 
osteoarthritis, and heart disease, 

THE IMPORTANCE OF THE RHEUI-lilTIC AND METABOLIC DISE/VSE PROBLEM 

No diabetic, treading that narrow pathway between insulin shock on the 
one hand and diabetic coma on the other, and, most certainly, no crippled victim 
of arthritis, vjould agree that any recitation of mortality statistics could 
possibly portray in any really effective way the tragic impact of the rheimatic 
and metabolic diseases upon the lives of millions of people in the United States t 

The outstanding single fact about m.ojiy of these diseases is that most 
of their viatims continue to live — they have to live with their afflictions, 
agonizing as they may bo. Some of these disorders, particularly rheumatoid 
arthritis, may totally disable their victims, leaving them burdens to themselves 
and dependent on others, Vlhen they die, however, it is some other disease which, 
sometimes mercifully, carries them off, 

^ut not all victims of rheumatic and metabolic diseases are crippled, 
disabled, or even severely restricted in their daily activities, for there is 
much, medically, which can be done for many of them. 



- 5 - 

Thus it is the "living rate" and not the "death rate" that is significant 
in assaying the impact of these diseases upon thu economic and social fabric of 
the United States community. It is with the millions of individuals in this 
country who are "living" with their diseases that we are concerned - the 10 
million who suffer in varying degrees the disabling effects of arthritis and 
rheumatism, the 2 million diabetics, and the uncounted niimber suffering from 
other metabolic diseases. And it is not only those who have these diseases who 
suffer the consequences. Those who live with, care for and support the victims 
are directly affected economically, emotionally, socially, and in many other 
ways . Thus xre can postulate, on the basis of an average family of three 
members, that roughly 2^ percent of our popula.tion is directly affected. Rare 
is the family which has not suffered invasion by one or more of the rheumatic 
or metabolic diseases. 

The Rheumatic D iseases. More people are crippled and incapacitated by 
the rheumatic diseases than by any other chronic disease entity. Of the 
10 million who are afflicted, approximately one million are permanently 
disabled, ■'onable to work or to support themselves. The total economic 
burden of these diseases is more than a billion dollars a year. Of this 
amount, more than 770 million dollars in wages and salaries is lost by those 
uaable to work, and it costs the taxpayers more than 103 million dollars for 
welfare and relief allox-jances. The Federal government loses, in income taxes 
alone, 28[i million dollars a year because there are more than 576,000 wage 
earners constantly out of work due to the disabling effects of arthritis and 
rheumatism. 

Diabetes and Other Metabolic Diseases . Of the chronic diseases which 
cause death in adults, diabetes is exceeded as a cause of death only by 
cardiovascular diseases and cancer. It is estimated that 25,000 persons die 



- 6 - 
yearly as a direct result of diabetes and that an additional 25,000 persons 
die yearly as an indirect result of this disease. 

It is currently estimated that inore than 2 million peoples ±n. the 
United States, or about 13 out of every 1,000 persons, have this serious 
crippling disease. It is lilcely that the prevalence rate is sloxirly increasing 
partly because of the increasing average age of the population. 

It has been estimated that diabetics are disabled about 15 percent of 
the tiine, which xvould mean approximately 300,000 man-years lost to productive 
effort each yea.r. In addition, some I;00,000 life-years are lost yearly because 
of premature deaths, ^t le-^st a quarter of these in the most productive period 
of life. The medical care problem is a grave one. It has been estimated that 
for the country as a whole diabetes costs its victims 1^0 million dollars 
yearly above normal living expenses. 

Figures for the incidence of and mortality rates from the other 
metabolic disease are not available. It appears probable, however, that 
metabolic defects Tjhich cause partial incapacitation, as well as those which 
cause death, are much more common than is usually supposed. One e^cpert, on 
the basis of observations in his own hospital, has estimated that one in 
1,000 infants suffer from a single, invariably fa.tal, metabolic disease known 
as pancreatic fibrosis or mucoviscidosis. 

ADVA NCES AGAINST RHEUI-g.TIG DISEASES 

Since the discovery in 19h9 that cortisone, a hormone of the adrenal 
gland, would dram^atically relieve rheumatoid arthritis, progress against the 
rheumatic diseases has been rapid. The advances in the past 7 years have been 
greater than those in the preceding 500. 

An interim statement concerning another important discovery in the 
field of the rheumatic diseases was m.ade to this Gomm.itteo last year. It was 



- 7 - 

ny privilege to report to you at that time that clinical investigators at the 
National Institute of Arthritis and Metabolic Diseases had tested two new, 
extremely promising drugs against rheumatoid arthritis. These drugs are 
called prednisone and prednisolone (the former names were metacort a ndracin 
and mctacoirtandralone) . As indicated last year, the importance of these 
drugs lies not only in their superiority over cortisone and hydrocortisone, 
but also in the fact that they demonstrate even wider horizons ahead — that 
even bettor antirheumatic agents can and will be found. 

The original findings were these: that prednisone was four times more 
potent than cortisone or hydrocortisone; that it was a very effective anti- 
rheumatic agent; that it did not cause such troublesome effects as sodium 
and water retention or potassium loss; that it brought pronounced relief to 
arthritics who had stopped responding to cortisone, hydrocortisone, or ACTH. 
These preliminary findings have since been amply confirmed by hundreds of 
physicians in this country and abroad who have administered prednisone to 
thousands of patients. The advantages of prednisone are so evident that it 
is currently replacing cortisone and hydrocortisone. 

Prednis one Studies Extended . During the past year, studies by National 
Institute of Arthritis and Metabolic Diseases investigators have bean extended 
to other rheumatic diseases besides rheimiatoid arthritis. The clinical, 
hormonal, and metabolic effects of prednisone in groups of patients vjith acute 
rheumatic heart disease, systemic lupus erythematosus, and scleroderma have 
been recently completed and reported in scientific journals. In all these 
diseases the new drug was found to produce striking improvement without 
causing disturbances in the delicate mineral balance of the body. 

Prednisone, however, is not altogether free from serious side effects, 
nor can it be regarded as a cure for any of these diseases. For these reasons 



- 8 - 

the search for a still more satisfactoiy drug — one that would be relativeliy 
free of undesirable reactions and yet retain potent antirheumatic properties ~ 
is being actively conducted. 

Another New Drug Tested . A new synthetic compound which differs from 
prednisolone by only one fluorine atom has for the first time been subjected 
to clinical trial at the National Institute of Arthritis and Metabolic Diseases, 
Ten patients with rhe\imatoid arthritis were given this steroid. Results indicated 
that it was 5 to 10 times more potent than prednisone or 20 to Uo times more 
potent than cortisone, but, unfortunately, it caused marked retention of sodium 
and xijater and severe loss of vital potassiimi salts. For these reasons this 
drug will not be clinically useful in the treatment of rheumatoid arthritis 
and other rheumatic diseases. It may have an important place, however, in the 
management of certain disorders of the adrenal cortex, such as Addison' s disease 
and the adreno-genital syndrome e 

Action of Steroids in Body Studied , Concurrent with these clinical 
studies, more fundamental laboratory research work has been done at the National 
Institute of Arthritis and Metabolic Diseases* Employing more accurate methods 
than have been available previously scientists have measured the precise amount 
Df hydrocortisone that the normal human adrenal cortex synthesizes daily as 
<iell as the rate at which this hormone disappears from the blood into the liver 
and out through the kidneys ^ The enzyme systems in the liver that are responsible 
for inactivation of lydrocortisone and similar hormones have been defined. This 
new knowledge will lead to a better linderstanding of how the body normally 
iisposes of the steroids it synthesizes. It also will offer a sound basis for 
Tiore intelligent administration of this compoimd to patients with a wide 
variety of diseases. 

Diagnostic Test For Arthritis. Work on the development of a diagnostic 



" 9 - 
test for rheumatoid arthritis, called the sheep cell agglutination test, is 
progressing* Scientists at New York University and at the University of 
Colorado, supported by National Institute of Arthritis and Metabolic Diseases 
grants, as well as investigators in our own laboratories, have been making 
steady advances both in refining the test and in learning more about the 
mechanisms involved. This test promises to be of considerable importance in 
confirming the diagnosis of rheumatoid arthritis and may throw additional 
light on the nature of the disease itself. 

Obese Mice More Prone to Osteoarthritis . Grantees at Washington 
University in St. Louis, studying joint disease of mice, have found that 
animals fed a high-calorie hign-fat diet are more prone to develop degenerative 
joint disease (osteoarthritis) than animals which are underfed. These findings 
add to our store of knowledge concerning the relationship of diet, and of 
obesity, to arthritis, 

Rhe\3matic Disease in Svjine . At Purdue University grantees have been 
studying a chronic arthritis of swine which shows many similarities to 
rheumatoid arthritis in the human. Studies of this disease in these animals, 
although it is not exactly the same as the human variety, may facilitate a 
better understanding of the corresponding disease in man. The disease as 
manifested in swine is caused by an infection. Experimental inoculation of 
swine with the infective organism produced death in 35 percent of the animals, 
and of the survivors 50 percent developed chronic arthritis. IiJhen normal 
animals were subjected to a vaccine from the organism and later inoculated 
with the live bacteria, the death rate was markedly reduced but the incidence 
of arthritis which developed in the survivors was between 90 and 100 percent. 
These findings suggest that in this type of arthritis, sensitization is 
important in the causation of the disease. It was also noted that swine with 



- 10 - 
advanced co.ses of this arthritic disease responded vary well to cortisone 
therapy . 

Progress Against Gout . Encouraging progress is being made toward 
clarifying the nature of the metabolic error which causes excessive accumula- 
tion of uric acid (sometimes 10 to 20 times the amount found in normal persons) 
in the blood and tissues of persons suffering from gout. Using a compound 
known as AIC, scientists at the National Institute of Arthritis and Metabolic 
Diseases have found that this substance is incorporated into uric acid in the 
hum.an. These studies arc being continued with the hope of improving the 
management of gouty patients as xvell as bringing about a better understanding 
of the development of the disease. 

Rehabilitation of Arthritics , Bed-ridden, practically helpless people 
left crippled by arthritis arc walking again; former "unemployables," disabled 
by the same disease, are now working every day as a result of intensive applica- 
tion of new and improved rehabilitation procediircs by a grantee at New York 
University. Of 17 severely disabled arthritis patients in one group, 13 have 
been discharged from the hospital. Six of these are now self-sufficient, the 
other 7 partially so. Of 21 less severely crippled patients all have been 
discharged from the hospital; 16 art self-sufficient and 5 are partially so, 

ADVANCES AGAINST DRBETES 

The modern attack on diabetes began with the discovery and isolation 
jf insulin, the hormone derived from the pancreas, in 1922, Since a primary 
cause of diabetes is the failure of the pancreas to form and secrete suf- 
Cicient insulin, the isolated hormone has been of critical importance in 
controlling the disease, 

A second milestone in our londerstanding of diabetes was the discovery 
by Houssay in 1930 that this disease may not always be simply a lack of insulin. 



- 11 - 

but may in part be related to the overproduction of other hormones . Houssay' s 
classical experiment was the demonstration that the removal of the pituitary 
(a gland found at the base of the brain) from a dia.betic animal caused the 
manifestations of diabetes to disappear. Since this operation did not increase 
the supply of insulin which these animals received, it followed that the lack 
of adequate insulin had not been the sole cause of their diabetes. 

Milestones in our understanding of disease processes, such as those, 
Rppear infrequently. It may be many years before auiothcr such striking advance 
in the field of diabetes occurs. Nevertheless, very real progress is made each 
year, and the past year has been no exception. 

D iabetic Acidosi s. Investigators in the National Institute of Arthritis 
and Metabolic Diseases have made important observations concerning diabetic 
acidosis, well recognized as a serious complication of the disease which can 
lead to coma and dea.th. During episodes of acidosis patients are often 
extraordinarily unresponsive to insulin. One pa.tient recently studied received 
21,000 units of insulin in 2)4 hours x^rithout discernible effect (in general, a 
severe diabetic would normally receive no more than 100 units). It has now 
been shovm that during diabetic acidosis there is a material in plasma which 
suppresses or abolishes the effect of insulin. This material is associated 
with certain of the proteins in the plasma, and does not appiear to arise from 
bacteria (many patients with acidosis have infections) or from the patient's 
adrenal gland. It is possible that it is secreted by the pituitary gland. 
These studies arc continuing. It is hoped that they viill help to explain 
variations observed in insulin requirements and will lead to improved treat- 
ment of patients with diabetic acidosis. 

At the Joslin Clinic and the Harvard School of Public Health, National 
Institute of Arthritis and Metabolic Diseases grantees have recently shown 



- 12 - 
that thera is o.lso a marked increase: of largu lipoprotein molecules in the 
blood during diabetic acidosis and that this disturbance is even more marked 
in diabetic coma. Upon treatme'ut with insulin, there is a correction of the 
lipoproteins toward normal levels. Since hi^h levels of these materials in 
the blood have been tentatively incriminated in the development of arterial 
disease, and since young diabetics not infrcquejitly develop this complicaticn, 
these findings may throw some lifht on this condition as well as upon the 
natural history of diabetes itself. 

Kotabolic D efect in Eyperirnental Diabe tes. National Institute of 
Arthritis and Metabolic Diseases investigators have discovered a metabolic 
defect in experimontol diabetes. Rats made dirbetic vrith a chemical which 
destroys the insulin-producing cells of the pancreas (alloxan), cannot 
transform the essential amino acid, tr^Tptophanj into the B-vitamin niacin, as 
normal animals do. As a result these diabetic animals must bo given larger 
than usual amounts of niacin in their diet. Further studies have shown that 
the livers of siich diabetic aniiaals contain a tremendous excess of two enzymes 
which are involved in the transformation of the amino acid into the vitamin. 
It h'^s also been shown that when insulin is administered to such anijiials, the 
metabolic defect is overcome, and the liver enzyme levels return to normal. 
It is not yet known whether similar metabolic defects arc present in human 
diabetes. 

Diab etic Retin opathy . Scientists at Jolins Hopkins University have 
discovered a connection between the eye changes brought about by diabetes, 
(diabetic retinopathy) and the ability of the affected individuals to utilize 
vitamin B-12, Following test dcses of this vitamin, diabetic subjects with 
eye changes excrete significantly more of the vitamin than non-diabetics, 
whereas diabetics without eye changes excrete considerably less of the. vitamin 



- 13 - 
than do non-diabetics. These findings su:j\':iest some as yet vrndiscovered re- 
lationship between vitamin B-12 and diabetic retinopathy, 

"Cortisone Diabetes" . It has been recognized for some time that 
hormones secreted by various endocrine glnnds may have complex interactions 
and affect each other. For example, ACTH produced by the pituitary gland 
stimulates the secretion of cortisone by the adrenal gland. Investigators 
at Jefferson Medical College have studied a type of diabetes caused by in- 
jections of cortisone in experimental animals. Not only is there elevation 
of blood su^ar and loss of sugar in the uririe of these animals, but studies 
of the pancreas show changes in the number and size of the cells which noiTnally 
produce insulin, A University of llinnesota grantee has confirmed and con- 
siderably extended these findings, Tliese results afford some explanation for 
the observations in clinical medicine that cortisone adjninistration may have an 
adverse effect on a diabetic state. They also serve to point up the fact that 
different metabolic disturbances and defects are interrelated and that progress 
in all metabolic diseases is dependent on studies of metabolism. 

Synthesis of Portions of Insvilin rIolecu.lc . As reported last year, the 
complete structure of insulin has been determined. Tliis important work, 
carried out in England, has opened the door to new and important research 
efforts in this country and elsewhere. An undertaking now underway in our 
laboratories at Bothesda is to synthesize certain portions of the insulin 
molecule. In the case of other protein hormones, such as thyroglobulin from 
the tli^'-roid gland and ACTH from the pituitary, the effective portion of the 
molecule has proved to be only a small part of the total. We cannot be certain 
that such is the case with insulin, and it is in fact iiuprobablc that we shall 
be entirely successful in synthesizing a small molecule which will substitute 
completely for insiiljji. Nevertheless, this result is possible, and in any event 



- Ii4 - 

the compoimds obtained should be extreinely useful iii studies concerning the 
action of insulin and its relationship to molecular structure. 

R adioactive Insulin . One of the most useful single experiraental 
devices in medical and biochemical research in the past txrenty years has been 
the introduction of isotopic labels — i.e., an atom which is radioactive or 
otheri'jise readily identifiable, A radioactive insulin would be most valuable 
in investlj^aticn of the site and mechanism of action of this hormone. At- 
te:::pts to prepare such a material have been unsuccessful in the past. A new 
attempt is now underway in our laboratories at Bethesda, depending in this 
instance on the perfusion of radioactive amino acids throurh the pancreas. 

Diabetes and Adrenal Steroids , In the Chronic Disease Prograpi of The 
Bureau of State Services, in addition to their importajit pioneering studies 
of screening techniques to detect early diabetes, other studies are undert'jay 
on the diabetes of pregnancy. In these latter studies, by an extensive and 
intensive screening prograia, pregnant women are divided into three groups; 
non-diabetic, marginal or pre-diabetic, and frankly diabetic. Collaborative 
investigations are now underway between this group of workers and others in 
the National Institute of Arthritis and Metabolic Diseases to determine what 
relationship, if any, exists between the enhanced adrenal function during 
pregnancy and the development of diabetes, 

OTHER ADYANCBS AGAIN ST II5TAB0LIC DISS/^SES; RSSa^iR GR IN MEL.BO LISM 

As has been noted, some metabolic diseases are well-studied and xjell- 
def ined, while others are only today beginning to receive the attention they 
deserve. Among the latter are inherited metabolic diseases xjhich afflict 
infants and children, such as galactoseiTiia and pancreatic fibrotic diseases, 
both mentioned earlier in this statement. 

It should be noted further that significant progress in the metabolic 



-15 - 

diseases can be achieved only by a broad, multidisciplined attack on metabolic 
problems as well as a stuc^ of the clinical manifestations of the diseases 
themselves. 

Cause of Fatal Disease of Children Fp-und . National Institute of 
Arthritis and Metabolic Diseases investigators have discovered the basic 
metabolic defect causing a rare, inherited, metabolic disease of children 
called galactosemia. Appearing in the first few days after birth, the dis- 
order is characterized in infants by an intolerance toward milk, and more 
specifically toward the sugar of milk, lactose. Lactose contains the sugar, 
galactose, as well as glucose. It is the galactose which the affected child 
cannot tolerate. If milk is fed to such children they become extremely ill. 
The illness manifests itself by diarrhea, lack of appetite, loss of weight, 
jaundice, and, if unrecognized, leads to cirrhosis of the liver, mental 
retardation, blindness due to cataract, and death, Oiir investigators have 
shown that the reason for this metabolic insviff iciency is a congenital lack 
of an enzyme which they discovered in normal red blood cells. This enzyme 
catalyzes o^^s of "the steps in the conversion of galactose to glucose (the 
sugar of the blood). The absence of this enzyme in red cells would appear to 
constitute a specific diagnostic test for the disease. Early recognition of 
galactosemia is extremely important since the affected child will grow and 
develop normally if kept on a galactose-free (milk -free) diet. 

The significance of this work lies not only in explaining the basic 
cause of a metabolic disease — it also promises to provide a rather simple 
test which will permit exploration of the possibility that impairments in 
galactose metabolism may be the causative factor in other disorders such as 
certain presently obscvire types of mental retardation, liver cirrhosis, and 
opacity of the lens of the eye. 



~1S ^ 

Simple Treatment of Burn Shock . One of the major advances in medicine 
durinf]; the past 2^ years has been the development of an effective treatment 
for shock, which in the past has caused countless deaths following b-urns, 
blood loss and other injuries. The treatment, involving the intravenous 
administration of whole blood, plasma, or the so-called plasr.ia extenders, has 
been most successful. The difficulties involved in intravenous therapy where 
lar^s numbers of individtials are involved, however, are trGmendcos and 
generally recognized. Extensive clinical tests conducted by "National Listitute 
of Arthritis and Metabolic Disea.ses invcsti^iators have now confirmed conclusions 
from laboratory tests conducted at the Institute several years ago that the 
adm.inistration of a simple salt and soda solution hj mouth is effective and 
safe, as compared to other methods of treatment of burn shock. Oral salt and 
soda therapy is inexpensive, sii;iple, easily adiiiinistered, and the materials 
required are readily available — ordinary baking soda and table salt, Tliis 
form of burn shock treatment is regarded as being of particularly great 
potential usefulness, especially in event of a major disaster, 

Wew Pain-Relieving Drug . Tlie separation of pain-relieving power from 
addiction liability, retaining the former and suppressing the latter, has been 
an objective of chemists and pharmacologists for iTia.ny years. Success in this 
endeavor, to any iiniDortant degree, has not been achieved among the man3'- known 
derivatives of morphine, or the nex-j SjOithetic drugs. Yet interest in this 
possibility continues and it is a noteworthy event when a pain-relieving power 
quantitatively siiTiilar to morphine can be demonstrated in a new chemical type. 
National Institute of Arthritis and Metabolic Diseases chemists have produced 
such a compound, designated as 5-(iTi-lT5rdroxyphenyl) 2-raethylmorphan, Its 
synthesis is being improved so that it can be tested for addiction liability 
and, if indicated, produced for clinical trial. 



- 17 - 

Sterilizer Foimd to Damage Food , Ethylene o::ide is a chemical widely 
used in industry to sterilize food in situations where steam or other con- 
ventional methods cannot be used. National Institute of Arthritis and 
Metabolic Diseases investi^-ators have demonstrated in their investigations 
that this chemical causes marked nutritional damage largely by destroying the 
B-vitamins, even though all of the chemical is removed after the treatment. 
The significance of this work extends beyond a mere demonstration of the 
damaging effect of a chemical. It also points out a largely neglected aspect 
of the safety'" of chemicals used to treat food, Tlie study shows that it is 
possible for a compound to damage food even though all traces of it are 
eliminated before it reaches the consumer and, by criteria, ordinarily applied, 
can be considered safe for use, 

300 Times as Sweet as Sugar , Carbohydrate chemists at tlie National 
Institute of Arthritis and Metabolic Diseases, searching for starting materials 
for the synthesis of medicinals, have extracted from a uniqtie small plant Imown 
as "The Sweet Kerb of Paraguay" a substance which is 300 times as sweet as 
table sw^ar. The substance, called stevioside, had been found to be coraposed 
only of carbon, lydrogen and o:xygen, and contains, as part of a large molecule, 
three units of glucose. It is not only the sweetest natural product yet found, 
but the only substance of high sweetening power which does not contain 
nitrogen. This item is reported as one of interest even though it is not 
anticipated that this material will compete xjith saccharin or with the avail- 
able synthetic sweetening agents, 

SIGNIFICANT PROGRAM DEVSLOR-'IENTS 

Research Grants , During the five years in which appropriations for 
research grants have been available to this Institute, there has been a 
remarkably increased activity in the fields of arthritis, diabetes and other 



- 18 - 

metabolic diseases, ^uring 19^6, I480 active research grants are expected to 
be in progress and the projects are located in over 100 institutions in 37 
states, the District of Columbia and Puerto Rico, During the coming fiscal 
year we plan to support additional worth-X'jhile research projects in similar 
program areas. It is believed, further, that the broad field of endocrinology 
is an extremely important one and deserves greatly increased attention and 
support, A most desirable goal is the exact determination of the output of 
individual steroids and other hormones from all the glands of internal 
secretion, both in normal individuals and in those suffering from arthritis, 
diabetes and other metabolic defects. The achievement of this goal would make 
possible tremendous advances in our understanding of boc^ processes and of 
many disease entities. 

Training Grants and Fellowships , One of the major program advances 
in the past two years has been the institution of postgraduate training grants 
in diabetes and other metabolic disorders and in arthritis. This program was 
started in a very modest way in 1955 in recognition of the acute need for the 
training of additional medical personnel who would be qualified to give the 
best type of medical care to arthritics and diabetics, With additional funds 
available in 1956, approximately 3U grants are to be awarded to accredited 
schools for the improvement of instruction, and approximately 65 clinical 
tralneeships will be awarded to individuals for specialized postgraduate 
training, 

Research fellowships are awarded to individuals to increase the number 
of scientists qualified to carry on independent research in the basic sciences 
as well as in the clinical area. This program has been of very great value 
in increasing the research potential in arthritis, diabetes, other metabolic 



- 19 - 

diseases, and in metabolism. Thirty-four fellowships are being supported in 
1956, and we expect to double this nxmber, approximately, in 1957» 

Intramural Research , ^ part of the inciBase in the 19^6 appropriation 
for research in our laboratories was utilized to inaugurate a well-rounded 
and effective program in diabetes and related metabolic disorders, Xhis 
program is T-jell unden^ay and is producing results of importance. Another 
portion of the 1955 increase was used to strengthen our basic studies in 
metabolism, so necessary for the solution of clinical problems concerning 
metabolic diseases. Effective use has been made of this opportunity. Mo program 
expansion over 1956 is proposed for 1957 in intramural research, save for the 
continuation of the progressive strengthening of investigations in the 
Clinical Center, 

COMCLUSIOMS 

During the past year notewortly advances have been made in the rheurdatic 
and metabolic disease areas. Particular mention should be made of the proof 
of effectiveness of the new steroid prednisone, not only in rheugiatoid arthritis 
but also against such related diseases as rheumatic heart disease, scleroderma 
and lupus erythematosus j of the discovery of the presence in the blood of 
diabetics during episodes of acidosis of a compound which antagonizes insulinj 
and of the definition of the precise metabolic defect in galactosemia, a faj:nilial 
disease of children. 

New fields, both in the area of basic metabolic research and in the domain 
of clinical medicine, have been opened to further e::ploration. As a result, 
there has never been a time more propitious than todaj'- for extending our research 
gains and for applying our new knowledge to the furtherance of human welfare, 

^'.''■■;r'oroi;l \/Z 5 
Prepared 1/25/56 



OPENING STATEMENT 
By 
Dix-octor, National Cancer Institute 
Public Health Service 

COMMITTEE ON /^PROPRIATIONS 

1957 ESTIM/vTE 

for 

"Salaries, Expenses, and Grants, National Cancer Institute, 

Public Health Service 

Mr. Chainian, Members of the Cor,iinittee : 

HISTORICAL BACKGROUND 

The National Cancer Institute v/as established by Act of 
Congress of August 5> 1937; for the purpose of achieving control of 
cancer in nan through studios relating to the cause, diagnosis, and 
treatraent of neoplastic diseases, and by supporting usef\xl applica- 
tion of the results of such studies. 

Although cancer research has expanded most rapidly since the 
end of World V7ar II, the Public Health Service has been active in 
the field since 1922. At that tine cancer research within the 
Public Health Service was initiated by two groups of scientists -- 
one at Harvard University and the other e.t the Hygienic Laboratory 
in Washington. These groups v;ere merged to form the nucleus of the 
National Cancer Institute. Under authority of the organic act of 
1937; the chief provisions of which v/ere incorporated in Public Law 
UlO, the woi'-k of the Institute is divided into two broad areas of 
activity -- the acquisition of knowledge about cancer, and the dis- 
semination and application of such knowledge. In the first area, 
the Institute conducts original research, both basic and clinical, 
in its own laboratories; supports research by individuals in other 
institutions and organizations througli grants-in-aid; and helps 
enlarge the supply of qualified research investigators by awarding 



fellowships to promising young scientists. To secure the widest 
possible dissemination and application of cancer knowledge so ac- 
quired, the Institute provides for grants, consultations, and demon- 
strations within the States; provides teaching grants to approved 
professional schools of medicine, dentistry, and osteopathy; awards 
traineeships to young clinicians; and distributes professional and 
lay educational and infonnational materials. 

The responsibility for scientific investigation of the prob- 
lem of cancer which our Government has taken upon itself has led us 
through several years of the most fruitful research in the v?hole of 
medical science, and opened up avenues of study v/hich are full of 
promise for the ultimate conquest of this burden on mankind. I say 
this in full appreciation of the fact that progress in this kind of 
research often appears to be agonizingly slow and seemingly un- 
related to the realities of the impact of cancer upon our people. 
Yet, when one looks back over even so brief a period as a year, one 
can, without difficulty, chart the progress made and note the 
general direction of our course . 

The Members of this Committee are vrcll aware that the Na- 
tional Cancer Institute is responsible for the acquisition of cancer 
knowledge through research and the application of this knov/ledge to 
the problems of prevention or treatment of cancer. They are 
familiar, too, vri. th the fact that the Institute performs both non- 
clinical and clinical research, and gives financial sitpport to 
research in non-government institutions. From both the intramural 
and extramural research areas have come important developments in 
the last year on vfhich I ani pleased to have the opportunity of 
reporting, though necessarily in rather brief form. 



- 3 - 
RESEARCH APPROACHES 

There are four central research approaches to cancer. The 
first is selective destruction of the cancer cell by a chemical 
which does not damage the surrounding heal-ftiy, normal tissues. 
Chemotherapy studies are pursuing this line of investigation. The 
second is use of radiation to do the same. The third is analysis 
of the physical, biological, and chemical nature of the structure 
and behavJ.or of constituent parts of the cell leading to blocking 
certain actions or substances related to the cancer process. Fourth, 
chemicals and other physical agents involved in our every-day living 
which are suspected as causing cancer are being sought and found. 

Finally, cancer can be attacked not only by research but by 
more effective application of what is already known. This involves, 
for example, the use of cytologic techniques as diagnostic tests to 
disclose the presence of cancer in the earliest stages. 

This Committee is rightfully and understandably concerned with 
the extent to which these approaches are being employed, and the 
degree of success being attained. 

CHEMOTHERAPY 

The past year has witnessed an intensive and productive effort 
in the field of chemotherapy, an area in which this Committee has 
displayed a keen interest. The Committee may recall that in recent 
years a handf\£L of compounds have been discovered which afford a 
considerable measure of relief from certain types of cancer such as 
Hodgkin's disease, leiikemia, and cancer of the breast and prostate. 
Nitrogen mustard compounds, 6-mercaptopurine, cortisone, and a few 
other names may be familiar to you. These chemicals have been 



- k - 

culled from many thousands, and a substantial part of this exten- 
sive screening has been done at N.C.I, 

Occasionally these drugs will halt the progress of the dis- 
ease for remarkably long periods. By determining the essential 
reasons for differences in the period of effectiveness, scientists 
were able to get a better understanding of the intricate relation- 
ships between these chemicals and the metabolic, life processes. 
These successes, modest though they were, were so loaded vdth po- 
tential that more concentrated and coordinated investigation in 
chemotherapy seemed not only desirable but inevitable. Therefore, 
with the aid of this Committee, the program of research grants and 
contracts in this field has been expanded considerably. More than 
200 research projects are being supported and, together with con- 
tracts for program services, about 5 million dollars have been 
invested in cancer chemotherapy research. The program has been 
strongly implemented by the establishment of the Cancer Chemotherapy 
National Service Center at the National Cancer Institute which, by 
providing research and informational services to cooperating scien- 
tists, serves to unify the effort. 

A chemotherapy program is a complex activity. Briefly, it 
consists of the following operations: First, nev/ chemical substances 
for evaluation against cancer must be made available by synthesis 
or by isolation from natural sources. Second, these materials must 
be screened for anti -tumor activity by proven methods, such as in 
animals, with bacteria, and in tissue culture. Third, those few 
substances of promise which have evolved from the screening process 



- 5 - 

must be thoroughly studied pharmacologically to make certain that 
they can be safely administered to humans with cancer. Fourth, the 
substances known to be both safe and highly active must be given a- 
careful clinical evaluation in man. 

The new Cancer Chemotherapy National Service Center has 
established such a program. The Center is an activity co-sponsored 
by the agencies, both government and non-government, cooperating in 
the chemotherapy program. National Cancer Institute employees 
directing its operation administer official Institute business con- 
nected with the program, and provide coordinating services for the 
entire effort. The Center is receiving hundreds of new compounds 
which have not been screened against cancer. They come from 
grantees, from industry, and from chemists in other cotmtries. 
Chemists have been helped to prepare new compounds by research grant 
support. In addition, the provision of chemical intermediates under 
the program saves the chemist's time for the difficult, final steps 
in drug synthesis. 

Panels covering different aspects of the program -- chem- 
istry, clinical studies, and others have been organized. They are 
composed of consultants who meet frequently. These panelists come 
from all sectors of our economy -- industry, government, and uni- 
versities -- and represent the most competent group of advisers 
available in their respective fields. 

Scientists of the National Cancer Institute in our intra- 
mural program in the Clinicol. Center are cooperating with five other 
groups in conducting clinical trials. These other groups are the 
Lemuel Shattuck Hospital in Massachusetts; Johns Hopkins Hospital 



- 6 - 
in Baltimore; the Georgetown University Hospital, here in Washington; 
Roswell Park Memorial Center, in Buffalo, N. Y*; and the Jackson 
Memorial Hospital, in Miami, Florida. 

Contracts have been let with five commercial laboratories to 
screen 2,000 new chemicals by June 30, 195^, and these laboratories 
will be able to test 5,000 chemicals during 1957. In addition, 
pharmacologic and toxicologic studios on a group of drugs will be 
Initiated this year by the Food and Drug Administration, using 
funds provi-ded by the Service Center. Meanwhile, the value of new 
screening techniques has been under study, both with research grant 
support and by contract. There is considerable hope that a cheaper, 
simpler, more effective screening system can be developed. 

Answers to the important questions which arise with evei'y 
new drug -- How lethal is it? How does it affect organs of the 
body? What dose should be used in the clinic? — are being sought 
through all of these approaches. 

Activity is great^ at present, in the antibiotic area. Some 
preliminary evidence at the preclinical stage suggests the usefiil- 
ness of a drug known as actinomycin-D. Also, some aromatic mustard 
compounds are being checked for any possibility of inhibiting tumor 
growth. In another current study, a pyrimidine antagonist, azauracil 
has been tried at the laboratory stage and seems to be effective 
against a sarcoma tumor in animals . 

The cooperative program is now in operation. There remains 
the task of seeing that each phase of the operation has the proper 
support, technical and financial, necessary to successful operation. 



- 7 - 
CYTOLOGY 

The Institute's progress in the application of cytologic 
techniques in discovering uterine cancer at the early, highly curable 
stage has been truly heartening. With the additional funds made 
available by the Congress, we will be intensifying our efforts to 
improve this technique and to determine the conditions under which 
it is most suitable. In addition, study is continuing in the search 
for means of enhancing the efficacy of various cytologic techniques 
for other sites, such as the lungs and the gastric area. 

To date, of 165,000 women over 20 years of age living in the 
Memphis, Tennessee area, about 100,000 have received the cell ex- 
amination test at least once on a voluntary basis, and in excess 
of U0,000 have retui-ned for a second check. Of these first 100,000, 
about 1,700 -- or slightly less than 2/o -- were considered suspi- 
cious cases. Most of these women volunteered for biopsy, that is, 
the microscopic examination of tiny bits of tissue taken from the 
suspected area. It turned out that more than 750 of them had 
uterine cancer. About ^50 of these were totally unsuspected. 
Another way of interpreting these figures would be to say that al- 
most two thirds of the cases detected by this procedure would not 
have otherwise been discovered until a much later stage. 

In addition to uncovering so many unsuspected cancers, this 
study strongly suggests that the condition known as carcinoma-in- 
situ (or preinvasive, early- stage, cancer) lasts long enough -- 
several years in fact --to permit effective curative treatment 
in practically 100 percent of cases if discovered at the yearly 
checkup . 



- 8 - 

F\irther research with the cytologic tv^chnique may answer a 
nvimber of questions bearing directly on the problem of controlling 
uterine cancer. Is the Memphis experience unique? Would results 
in the other comm\mities of different racial or other population 
patterns demonstrate as well the great usefulness of this case- 
finding procedure? What is the earliest age at which this lesion 
called carcinoma-in-situ shows up? Does this condition invariably 
lead to the invasive or late stages of cancer? What is the dura- 
tion of this early stage before invasion of underlying tissues 
sets in? 

To answer these and other medical questions additional centers 
will be started this year. They arc: 

Louisville, Kentucky San Diego, California 
Madison, Wisconsin Providence, Rhode Island 
Washington, D. C. Charlotte, Worth Carolina 
Columbus, Ohio Detroit, Michigan 

Other centers to be operated directly or by local institu- 
tions through grants are in the planning stage. 

It has been found that the grant mechanism is most effective 
for some centers, while for others it is better to have NCI person- 
nel boar principal responsibility for operation of a center. By 
establishing them in different parts of the country and serving 
different segments of the populations in those areas we will bo able 
to secure information that could not be obtained through centers of 
a standard pattern. The question of most effective size is also 
important. Current planning activities include determining the 
optimum size of the centers, population groups to be studied, and 



- 9 - 

whether the grant or direct operation mechanism should be adopted. 
As these screening operations proceed^ we will secure the data to 
corroborate or clarify our initial medical findings and be able to 
pass on our experience in center operations to local communities 
desiring to establish their own centers. Since the cytologic tech- 
niques are to be applied to sites in addition to the uterus, such 
as the intestines and the lungs, it is necessary to establish 
centers which will provide a large enough total population to make 
the results statistically significant. 

Fluorescent cytologic techniques are under active study. 
For example, one grant is investigating the possibility of injec- 
ting the patient with a fluorescent dye so that the cervical cancer 
will itself glow under observation with an ultra-violet light 
instrument. Another study is concerned with the possibility of 
staining the smear slide with a fluorescent dye. This would make 
for easier a.nd more accurate identification of the cancerous cells. 

Other related research is going on in this field at the same 
time. For example, the Institute is considering grant application 
which set forth means of making it possible for women to cooperate 
directly and quickly in collecting the necessary specimens of body 
fluid. A current grant project involves the development of an 
electronic device to sort out mechanically the large mass of nega- 
tive smears from the positive and suspicious ones. Such a machine 
should greatly reduce the number of trained technicians required for 
a screening survey and speed up the work. 

A series of new field studies are planned to include a gastric 
cancer study utilizing all of the currently available techniques -- 



- 10 - 
photofluorography, tubeless gastric analysis, and others -- among a 
group of patients with possible precursors of cancer. 

ENVIRONMMTAL CMCER 

The goal of research in cancer is, of course, eventually to 
prevent the disease from taking hold in the human system. Any 
device, statistic, theory, experiment -- is pointed toward discover- 
ing means of controlling cancer by preventive measures. It is, 
therefore logical to consider the field of environmental cancer 
strategic because of the potential for uncovering factors, sub-' 
stances, or conditions in our every-day life which may lead to more 
effective means of heading off cancer. 

This area is as broad as the activities of humankind. The 
diversity of approach to cancer research in the environmental field 
is well illustrated by five studies involving such a wide range of 
subjects as statistics, plastics, circumcision, allergy, and 
chromium . 

One of our field groups has been making a study of leukemic 
children. It has been observed that a number of the mothers had 
a pre-natal history of certain types of allergies. Although this 
study is new, and the number of mothers interviewed is small, this 
finding, even at this early stage, is considered to be statistically 
significant. 

The Institute has cooperated with the State of Connecticut 
in analyzing the detailed records of some 75^000 cancer patients, 
most of whom have been carefully followed over a period of some 17 
years. This study is unique because of the comprehensive medical 
records which were available. The data reveal a substanticJ. increase 



- 11 - 

in the ci.irG rate for both men and women, suggest that surgery is 
becoming more effective, and indicate that it may be possible soon 
to reduce the well-known 5-year "wait-and-see" period to a much 
lower period for cancers in certain parts of the body. 

The amazing absence of cervical cancer among women married 
to circumcized males, as noted nraong Moslems and Jews, for example, 
has led to a study comparing groups of women both in this country ' 
and in the Mediterranean area to discover any additional evidence 
which can explain this phenomenon. 

Studies over a long period of time have indicated that ex- 
posure to certain substances may cause cancer. These substances 
include chromium, asbestos, stainless steel, cutting oils, plastics 
and some petroleum products . Studies should be intensified to 
gather more facts about these substances previously investigated. 
More iiTiportant, perhaps, are investigations of substances which 
may be carcinogenic but of which we have little knowledge . 

These projects and experiments are representative of the many 
manrently under way or being planned in the field of environmental 
cancer. Our successes both in the laboratory and in the field 
cause us to look forward with definite optimism to the development 
of more effective means of diagnosing, controlling, and some cases, 
of preventing cancer. 

LABORATORY AKD CLINICAL R ESEARCH AT BETHESDA 

Last year the Committee heard a preliminary report from the 
Dix-ector of the National Microbiological Institute on research 
undertaken in collaboration with the National Cancer Institute to 
investigate the possibility of using certain viruses for the 



- 12 - 
treatment of cancer. This year we are able to report interesting 
and promising progress with this research, though results are not 
yet conclusive. In their efforts to develop a vaccine against 
illnesses generally termed "common colds" NMI scientists undertook 
to grow so-called APC viruses in laboratory cultures of uterine 
cancer cells. It was observed that the viruses ultimately destroyed 
these cells. Naturally, it was decided to find out whether they 
would also destroy uterine cancer cells in the humcji patient. We 
began by injecting small amounts of the viruses directly into the 
tumors of patients in the Clinical Center who had received other 
prescribed forms of treatment for their advanced disease without 
avail. The typical result was damage to the tumor, within a few 
days, at the site of virus injection. In order to get more of the 
viral agent to the tumor mass, injection through arteries was done 
as the second step. The third step was to combine both forms of 
injection. In all cases, although tumor dainage resulted, the effect 
was transitory due to the development of bodily resistence to the 
virus in the patient. A problem on which wc must work now is to 
produce enough of the viral agent and concentrate it sufficiently 
to permit the use of stronger doses. It is a very challenging 
problem to scientists of both the National Cancer Institute and the 
National Microbiological Institute, and one on which collaborative 
research will continue. 

The study just discussed is an example of the potentialities 
of the joint laboratory-clinical work made possible by the Clinical 
Center. Another study made possible by the new facilities also 
warrants comment. Our surgeons have noted the frequent reappearance 



- 13 - 
of cancer aroiiiid the incision after an operation. Realizing that 
stray cancer cells lodge themsolvos along these incision points 
and "seed" the wound for new cancer grov7th, means are being sought 
to thoroughly "wash" these areas with a chemical to eliminate such 
recurrence . 

Radiation, as you know, constitutes one of the most effective 
means of cancer therapy. Some new approaches to the dose -response 
relationship in treating cancer with x-rays are being made by our 
radiologists. Resialts to date suggest that the prolongation of the 
treatment period permits some increase in the administration of the 
total dosage without undue harm to the patient. 

In the area of general medicine, a cooperative venture is 
underway with several other research groups in an attempt to devise 
precise tests for measuring the therapeutic value of anti -cancer 
drugs . More and more experience and data are being accumulated in 
our clinical research with the occupancy of more cancer beds and 
the consequent availability of the kinds of patients needed to 
enlarge our studies and permit more comprehensive collaboration 
between nonclinical oxid clinical investigators. 

These are but a few examples of the steady progress that is 
being made through oiir intramural research program at Bethesda. 
ACCOMPLISHMENTS IN THE GR MT PROGRAM 

The National Cancer Institute has provided funds this past 
year for approximately 800 grants for research projects covering a 
wide variety of the medical and biological sciences. I can do 
little more at this time than identify a few, by way of illustrat- 
ing the nature and potential of these mcjciy studies being carried on 



- li^ . 

throughout the country by top scientific investigators. 

Viruses are relatively simple cells. The bridge between life 
and inert substances was shown many years ago when a living virus 
was converted into a crystalline form like a nonliving chemical and 
then shown to resume the o,ttributes of life upon replacement in the 
proper environment. Now it has been possible to separate such a 
virus into its two major components --a special protein and a 
nucleic acid. The amazing observation is that upon again mixing 
these two components under proper conditions, the virus reconstitutes 
itself so that it not only looks as it did before being disintegrated 
but is capable of infecting other cells and of reproducing, thus 
regaining the attributes of life . Such observations are important 
for cancer because of the knowledge of how cells live and reproduce, 
and because of the potential for understanding how other viruses may 
be causally related to cancer in animals, including man, and how to 
prevent or cure cancer. 

In a different type of study, bile from individuals with 
cancer of the bile duct has been injected into hamsters, resulting 
in tumors of the liver in some of the experimental animals . Since 
bile from normal individuals and from those suffering from other 
diseases had no such effect, this suggests the presence of some 
abnormal cancer-inducing component in the bile of persons with 
cancer of the bile duct. 

Hormonal factors have been involved in some investigations. 
In one, an almost 50 percent improvement was noted in a group of 
patients with advanced breast cancer when the ovaries and/or adrenal 
glands were removed. Improvement took the form of disappearance of 



f 

- 15 - 
pain, shrinkage of the tumor, and healing of ulcerations. 
PROMISING ARMS FOR MORE ESTENDED RESEARCH 

The National Advisory Cancer Council and the Institute staff 
have identified certain areas of i-esearch, which, it is felt, have 
great potential and should, therefore, be further explored. Among 
these are investigations of the role and extent of influences of 
viruses in causing cancer. The isolation, purification, and bio- 
chemical analysis of the virus causing a form of leukemia in chickens 
encourages the hope that further study may lead to some success in 
treating Hodgkin's disease, leukemia, breast cancer, and other malig- 
nancies. 

Radiation as a cause of cancer is part of the program for 
studying radiation effects in monkeys and other laboratory animals. 
This program has been stimulated and supported by the National In- 
stitutes of Health and the Atomic Energy Commission. Tlie role of 
hormones -- pituitary, adrenal, thyroid, and others -- in relation 
to the causation and growth of cancer should be more extensively 
investigated. 

In conclusion, I can indicate the necessity for continuing 
and expanding our efforts by noting some of the major trends in this 
disease as reflected in nation-wide studies over the past thirty 
years . 

(1) Cancer mortality has been increasing steadily among men. 
Since 1935 there has been a small continuing decrease in cancer 
mortality among women. 

(2) The increase among men is duo primarily to the very 
rapid rise in mortality from cancer of the limg. 



- 16 - 

(3) The decrease in women is due in large part to iniprove- 
Eients in the management of cancer of the uterus . 

(h) The data obtained from cancer registers indicate that 
there has been marked improvement in the survival experience of 
patients with cancer of the lai-ge intestine, rectum, uterus, pros- 
tate, and thyroid. 

The cancer death toll this year is estimated to be the rough 
eqtiivalent of the total population of a city the size of Richiaond, 
Virginia, Dayton, Ohio, or Oklahoma City. A recent estimate puts 
the loss in goods and services from cancer illness at somewhat in 
excess of 12 billions of dollars per year! 

In the face of this staggering picture, the modest successes 
and plans which I have briefly outlined take on added significance 
in terms- of potential for the ultimate conquest of cancer. I hope 
that this Committee shares the basic optimism expressed by the 
Surgeon General of the Public Health Service, when he said: "Cancer 
is not an unsolvable mystery of the universe. It is a practicol 
scientific problem, and science in its stride can conquer it." 



OPENING STATEMENT 

by 
Chief Dental Officer 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1957 ESTIMATE 
For 
"Dental Health Activities, Public Health Service" 



Mr, Chairman and Members of the Committee: 

Dental disease is a term used to refer to a broad spectrum of 
disorders of the teeth and their adjacent tissues. These disorders are 
generally non-communicable and chronic in nature. Their manifestations 
are diverse, including not only tooth decay but diseases of the gums, 
the cheeks and lips, the throat, the jaws and their related muscular and 
skeletal components. 

As I stated to this committee last year, no other disease category 
affects recurrently and constantly so large a proportion of the popula- 
tion. These defects currently cost the Nation more than fl.5 billion 
annually in consumer expenditures, plus millions more spent by govern- 
mental and voluntary agencies. Aside from the ill effects of dental 
disease on personal health, these disorders are frequently a cause of 
industrial absenteeism at a time when maximum use of manpower is essen- 
tial to our national economy. 

The best available evidence suggests that less thaji UO percent of 
the population receives adequate dental care. Since dental disease af- 
fects almost everyone, there is a resulting accumulation of neglect. In 
fact, it can be estimated that the number of hours which the dental pro- 
fession is able to provide each year is approximately one-seventh of the 
hours needed to correct the accumulated neglect existing at the present 
time. 



-2- 

Public concern over this problem was aroused during World War II 
by disclosures of the volume of Selective Service rejections for dental 
causes. The number of persons found unfit for service because of dental 
defects was approximately equal to the strength of three military divi- 
sions. That such concern has not led to substantial improvement is evi- 
dent from a military survey in 1955 » which revealed a persistent pic- 
ture of oral ill-health. Of every 100 inductees, 6 required upper den- 
tures, 11 lower dentures, 4-0 bridgework, and 4-5 some type of oral pro- 
phylaxis. Also, the average inductee needed five fillings at the time 
of examination. 

The dental health activities of the Public Health Service are 
directed toward the basic causes of this problem. Briefly stated, they 
are contributing to a solution: through extensions of knowledge of the 
biology of oral disease; through encouragement of wider application of 
preventive and control measures; and through fostering an increased cor- 
rection of dental defects by an expansion and broadened utilization of 
resources. 

It is generally agreed that the ultimate answers to the problem 
of dental disease must be found by research on etiologic factors, funda- 
mental tissue changes, metabolism, heredity, and epidemiologic techniques. 
From this research, we may reasonably expect the development of simple 
and economical methods for the prevention of these diseases. 

DENTAL RESEARCH 

Dental research, despite its obvious importance as a means for 
pointing the way to prevention and control of dental disease, has lagged 
for generations. The major deterrents to progress in dental research 



-3- 
have been (l) an Insufficiency of funds; (2) a shortage of trained in- 
vestigators; and (3) the absence of a mechanism for coordinating acti- 
vities in this field and for facilitating communication among researchers 
in dental and allied fields. Congressional authority establishing the 
National Institute of Dental Research in 194-8 enabled the Public Health 
Service to begin work in meeting these needs through a program of research 
grants, the award of fellowships, and the conduct of intramural reseai-ch. 
Research Grants ; The grants program of the Institute encourages inde- 
pendent dental research by stimulating the active participation of dental 
schools, hospitals, and other scientific institutions. The primary pur- 
pose of these grants is to support investigations which could not be 
undertaken if federal funds were not available. 

During the current year, the Institute is administering a grants 
program for the support of some k5 projects in 22 nonfederal institu- 
tions. The projects are concerned v/ith a number of vital but neglected 
problem areas, as for example, investigations of cellular respiration 
in dental tissues, the organic components of saliva as related to 
tooth decay, and the role of vitamin deficiencies in the causation of 
periodontal disease (pyorrhea) , 

At Yale University, the Public Health Service, through a re- 
search grant, is underwriting studies on the transplantation of embry- 
onic "tooth germs" into the eyes of experimental animals, where their 
further development can be directly observed. A finding of interest 
from this project is that methylcholanthrene , a cancer-inducing agent, 
was able to alter the microscopic appearance of the "tooth germs" to 
resemble that of malignant tumors. Another striking development has 



-4- 

been the recrystalization of tooth structure in a test tube by a gran- 
tee at the Jewish Hospital in Brooklyn. This points to the possibility 
of producing a synthetic filling material which is similar to the 
original tooth structure. 

The rapidly expanding need for grant support for dental research 
at this time greatly exceeds the present resources of the Institute. 
At its November meeting, for example, the Advisory Council recommended 
approval of 33 projects, which could not be activated through lack of 
funds, and 5 projects were awarded only half of the amounts required 
for their execution. It is likely that an additional niimber of requests 
will be approved at the February and June council meetings in 1956 with- 
out funds available to activate the projects. Thus, vre will be able to 
activate less than half of the approved applications during 1956. 

The increase requested in this budget for research grants will 
permit the support of a higher percentage of approved applications. It 
will also permit a broadening of the program and allow support of more 
long-term projects, goals which are in keeping with the suggestions of 
the Senate Appropriations Committee for last year. 

Research Fellowships ; The number of young dental graduates and students 
in the basic sciences preparing for a career in research is wholly in- 
adequate. The lack of financial support during training has been a 
major factor. The principal function of this part of our program is to 
assist promising students to complete their graduate studies. At the 
present time the Dental Research Institute's program can support about 
18 full-time fellowships at the pre-doctorate and post-doctorate level. 
Within the limitations of the current allocation for this purpose, we 



-5- 
are able to support only about 1 of every 3 qualified applicants for 
graduate training in the basic sciences. 

Besides the full-time research fellowship program, the Dental 
Institute supports \indergradua.te dental students on a part-time basis. 
These students work on research projects under the guidance of experi- 
enced faculty investigators. This program which was inaugurated in 
1955, is designed to attract dental students into careers of research 
at an early stage of their development. 

The increase requested for 1957 will augment the part-time stu- 
dent fellowship program and initiate a senior fellowship program. The 
latter activity will recruit a limited number of senior research workers 
into the dental field. Particular emphasis will be placed on supporting 
young scientists in the preclinical or basic science areas where the 
most serious shortages exist today. 

Intramural Research Activities ; Through the work of the Program Plan- 
ning Committee of the National Advisory Dental Research Council and of 
the Dental Study Section, principal gap areas in our knowledge of dental 
disease are identified. The content and emphasis of the Institute's 
intramural program are shaped by such information and by a policy of 
concentrating our resources on types of investigations which others are 
in a less favorable position to carry out. The Institute staff is 
therefore engaged in a number of studies involving costly facilities 
and a diversity of specialized competences which are available to few, 
if any, dental schools but are available at the National Institutes of 
Health. The structure of the National Institutes of Health facilitates 
a close integration of dental research workers with investigators in 
the biological sciences in the programs of other Institutes. 



-6- 

Research on the metabolism of ingested fluorides will be con- 
tinued, as for example, studies of the effect of fluorine on calciiom 
metabolism by use of radioactive isotopes. In connection with water- 
borne fluorides, the Institute recently completed a 10-year field 
study in two Texas towns. Medical and dental examinations of over 200 
residents showed that., with the exception of mottled enamel, no physio- 
logic changes ascribable to fluoride ingestion had occurred in persons 
using water with eight times the amount of fluoride recommended for 
carles control. Histological and chemical studies on human autopsy 
cases from high and low fluoride areas are continuing. New and more 
accurate methods for determining the fluoride content of blood and soft 
tissues are being developed. 

Employing the electron microscope, Institute scientists are in- 
vestigating the basic structure of the oral hard and soft tissues. 
Studies during the past few years have already added much new informa- 
tion about the protein or non-mineral elements of the teeth. During 
the coming year, we propose to refine needed technical methods and to 
gather essential data on the crystalline elements of normal and diseased 
teeth. The manner in which these crystalline elements can be altered 
will be investigated. 

Investigations aimed at evaluating the effect of certain dietary 
and nutritional factors in the cause of oral disease will be continued. 
Studies completed in the past year have shown that heat processing of 
protein foods, such as milk powders and cereals, will influence the 
production of experimental tooth decay. The results to date suggest 
that the effect is due to an alteration of the nutritional character of 
the diet. 



-7- 

Basic research on the biochemistry of periodontal disease vdll 
be carried on into the next year. Recent progress in methodology has 
broadened the opportunities for studyd.ng experimentally-produced 
periodontal disease in laboratory animals. These studies are de- 
signed to evaluate the chemical and enzymatic changes which occur as 
disease is produced in these tissues. As information is gained con- 
cerning these changes in the tissues of experimental animals, parallel 
studies are made on a limited number of diseased tissues of humans. 

The Dental Institute is al.so conducting several studies at the 
Clinical Center utilizing selected subjects from the ambvilatory group 
of patients seen in the outpatient facilities. Projects now underway 
on an outpatient basis at the Center include abnormal patterns of growth 
of the head in a series of nev/born and very young children; an evalua- 
tion of nutritional factors and high vitamin therapy in treatment of 
chronic stomatitis; a comparison of techniques for treating periodontal 
disease (pyorrhea); and an evaluation of the effects of high speed and 
ultrasonic cutting instruments. 

During the present fiscal year a limited number of beds in the 
Clinical Center has been made available to the Dental Institute, per- 
mitting the study of selected patients under carefully controlled con- 
ditions. Studies which have been inaugurated are: the effect of intra- 
venous vitamin therapy on the rate at vjhich oral tissues heal following 
surgery; the physiological effects of local and general anesthesia as 
used in dental practice; and studies on the excretion of fluorides by 
normal and diseased patients, particularly persons with cardiovascular 
or renal disease. 



-B- 
There is little doubt that saliva, in which the teeth and oral 
tissues are continuously bathed, is related to both dental decay and 
periodontal disease. Nevertheless, we have very little information 
about the nature of this relationship. Moreover, we have only a frag- 
mentary understanding of how general systemic conditions affect the 
relationship among constituents of the oral secretions. The slight 
increase requested in this budget for intramural research is for the 
purpose of expanding our investigations in this most important and 
promising area. 

PROFESSIONAL AND TECHNICAL ASSISTANCE 

In order to derive practical results from fundamental research, 
new developments in prevention and control must be adapted for State and 
community use. The public health procedures now available are not being 
used to their fullest extent. By demonstration or clinical evaluation, 
including the experimental testing of equipment, materials, techniques, 
and processes, the widespread adoption of new and proved public health 
techniques in State and communities is pursued. These activities, 
aimed at the prevention and control of dental disease, vdll be con- 
tinued at the 1956 level. 

Accordingly, studies of water fluoridation and defluoridation 
are being continued, as well as of the caries inhibiting effect of 
selected topical agents. Although most of the work in the development 
of new techniques requires several years of investigation to achieve 
results, some important accomplishments in this field can be reported 
at this time. For example, a special feeder has been developed for the 



;;f be. 



-9- 

purpose of dissolving calcium fluoride completely and continuously. 
Heretofore, it has been impossible to use calcium fluoride as a fluori- 
dating agent because of its insolubility in water. Should the field 
tests prove successful, the potential vdll exist for greatly reducing 
the cost of community water fluoridation. Calcium fluoride, which is 
plentiful, costs 2-3 cents per pound as compared with 7-8 cents for 
sodium silicofluoride and 12~13 cents for sodium fluoride, the two most 
commonly used fluoridating agents. 

Small chemical feeders, adapted for home use, have already been 
placed in operation in Montgomery County, Maryland, to examine problems 
associated with fluoridating individual water supplies. These devices 
have great potential for bringing the benefits of fluorides to more 
people . 

In addition to conducting developmental studies, this appropria- 
tion provides for consultation and assistance to states through a quali- 
fied dental staff in Public Health Service Regional Offices. Specific 
projects in such areas as personnel utilization, definition of dental 
problems, and dental clinic administration, pinpoint those features of 
dental program operation which have multi-State implications. Through 
these projects, patterns for the operation of realistic State-wide 
dental programs are developed and made available to States, States and 
communities call on the regional staff for assistance in program review 
and evaluation, and for suggestions regarding program modifications. 
By means of such consultation and technical assistance, we work v;ith 
State and local health agencies to bring the benefits of new knowledge 
and techniques to the individual citizen. 



-10- 
An impressive array of scientific evidence has established the 
safety, effectiveness, and practicability of water fluoridation as a 
means for reducing dental decay by as much as two-thirds. Despite the 
great promise inherent in this public health measure, its rate of accep- 
tance by communities has decreased somewhat over the past two years. In 
order to help put this knowledge to work, our program of making the facts 
about fluoridation known to State and IocelL health agencies, and of pro- 
viding them with technical assistance Ip the application of this measure, 
will be continued. 

DENTAL RESOURCES 
Until research and development ultimately furnish methods for 
substantially reducing the occurrence of dental defects, we must rely 
mainly upon an increase in the voliome of services received by all seg- 
ments of the population. The various elements in a program for expand- 
ing dental care, however, need careful evaluation and study. The Pub- 
lic Health Service therefore carries out surveys designed to yield * 
basic information on the supply of manpower and facilities, the utili- 
zation of dental personnel, and the financing of personal dental 
services. 

Manpower Supply ; There is evidence that effective demand for dental 
care is increasing as a result of broadened dental health education 
activities, and improved economic conditions. Parallel increases in 
the supply of dental personnel must occur if additional services are 
to be fxirnished. Although the number of dental graduates exceeds the 
number of dentists who die or retire each year, the population has 



-11- 

recently been growing at a greater rate than the number of dentists. 
Should this trend continue, dentist supply will be unable to keep pace 
with the expanding demand for dental care. 

The Public Health Service has therefore been active in the im- 
plementation and conduct of dental manpower surveys. These have in- 
cluded investigations of the financial status of dental schools, analy- 
ses of the costs of attending dental school, and studies of the need for 
new training facilities. In response to a request from one of the State 
Departments of Health, for example, the Service carried out a Statewide 
Survey of dental personnel needs. The resulting report, based upon an 
analysis of population trends, fiscal capacity, and population charac- 
teristics, recommended establishment of a dental school. F'urther recom- 
mendations were concerned with the location, university affiliation, en- 
rollment size, and estimated initial capital and annual maintenance 
costs for such an institution. Completion of this report has already 
been followed by additional requests. At the present time a comparable 
analysis is being made for 11 States and 2 Territories. 
Manpower Utili i!'ia-*'.ion; Since dentists, never available in numbers ade- 
quate to meet the dental needs of the Nation, are in short supply, 
strenous efforts must be made to utilize the present Bianpower supply 
with maximum efficiency and economy. Studies have already shown that 
effective use of auxiliary personnel can augment the dentist's produc- 
tivity. Efforts will therefore be continued to encourage improved 
utilization of auxiliary workers, and labor-saving professional 
techniques. 



-12- 
Financing ; In planning for the public's dental health it is necessary 
to keep in mind the great need for experiments and carefiil observation 
on methods of paying for personal dental services. Clearly, no logical 
purpose would be served by expanding dentists' capacity to produce ser- 
vices without concurrent means of assuring stable financing for the in- 
creased services. The Public Health Service has for this reason ini- 
tiated studies of the potentialities inherent in prepayment and post- 
payment plans as a means for widening the availability of dental ser- 
vice to a larger proportion of low and middle income groups. The prac- 
tical and growing necessity for such studies has already become appar- 
ent from the requests of State health officieils, dental societies, and 
medical care administrators for information and for results of operating 
experience . 

Increases in funds for 1957 have been requested to assist in 
accelerating and expanding the investigation of problems associated 
with the financing of dental care. To determine the applicability to 
dentistry of various methods of payment, we propose to imdertake two 
categories of research: (l) collection of actuarial data and develop- 
ment of prototypes for voluntary prepayment and post-payment plans, and 
(2) conduct of utilization and cost studies of dental care programs 
supported by labor and industrial organizations. 

SUMMARY 
The program which I have described has been planned as a co- 
ordinated approach for the improvement of the Nation's dental health. 
Its chief elements are the conduct and stimulation of dental research; 
the development and testing of preventive measures; the provision of 



-13- 
technical and advisory services to official health agencies and assi- 
stance in maximizing the supply and utilization of dental resources. 
In the implementation of this approach, we work closely with all the 
professional and voluntary groups dedicated to the betterment of dental 
health. 



!*:. ■ 



OPEt'ING STATEififlT 
by 
Director, National Heart Institute, Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1957 ESTIMATE 
for 
"Salaries, Expenses, and Grants, National Heart Institute, 
Public Health Service" 

Mr, Chairman and Members of the Committee: 

1955: 809,000 DEATHS FROM HEART DISEASE 

Fifty-three percent (809,000) of the estimated 1,527,000 deaths 
in the United States in 1955 were caused by heart disease. 

Generally speaking, "heart disease" Includes the cardiovascular 
diseases, a complex group of over 20 illnesses of the heart and blood 
vessels. Hardening of the arteries and high blood pressure and their 
consequences, like "heart attacks" and "strokes", play by far the great- 
est role, accounting for over ninety percent of the problem. Not to 
be disregarded, however, are such afflictions as rheumatic fever (which 
leads to rheumatic heart disease) and congenital heart disease (heart 
and blood vessel malformations present at birth) j even these number many 
thousands of cases and several thousand deaths each yearc 

While the major impact of heart disease lies upon the old rather 
than upon the younger age groups, heart disease Is by no means a problem 
only of the old person. One-third of all the heart disease deaths 
occur at ages under 65. 

Duriiig the past two decades (1933-52), the heart disease death 
rates for females have declined 20 to 45 percent, with the greatest 
savings at the younger ages o But the rates for m9.1es have Increased 5 to 
20 percent for the age groups 4.0 to 69, with the greatest Increase being 
at ages 45 to 59. 



- 2 - 

Among white men 45 to 59> *ver half of all deaths (52,9 percent 
in 1953) in the United States are caused by the various forms of heart 
disease, though chiefly from heart attacks— a result of the cardinally 
serious form of hardening of the arteries known as atherosclerosis. This, 
the major disease of our times, is receiving a concentration of research 
attention hitherto unparalleled and not even believed possible a few 
years ago, 

VVhile over-optimism must be strongly cautioned against, the belief 
is growing that the foreseeable future will bring very great gains against 
the problem of hardening of the arteries. Moreover, in another but related 
field, that of high blood pressure, cautious optimism is also justifiable. 
Here there is perhapo an even brighter glimmer of hope because of the 
advance of research in recent years. From 1950 through 1954 there appears 
to be a barely perceptible-downward trend in three causes of death which 
include hypertension (high blood pressure). These are, in statistical 
classification, deaths caused by "hypertension with heart disease", 
"hypertension without mention of heart disease", and "cerebro-vascular 
accidents". All three of these, incidently, include some elements of 
arteriosclerosis or hardening of the arteries. 

The available figures show that, comparing 1954 to 1950, there 
has been a slight decline in the death rates per 100,000 population from 
high blood pressure in the age groups 45-74. It is always dangerous to 
predict cause and effect with such short term evidence, particularly 
because problems of statistical interpretation, involving such things as 
coding and cause of death certification, enter the picture. Nevertheless, 
this may be the time to venture a little way "out on a limb" by suggest- 
ing' the possibility that we may now be seeing the beginning of the effect. 



- 3 - 
of new blood-pressure-lowering drugs. 

Recent discoveries and developments, such as those in drug therapy 
for high blood pressure, have added to the existing body of knowledge of 
various heart and blood vessel diseases. But the major advances toward 
full imderstanding have yet to be made. There is still today a lack of 
enough knowledge of basic causes or of preventive and curative treatments 
for many of the varieties of heart disease — and particularly the major 
forms. Before the greatest reductions can be made in the toll of untimely 
heart disease suffering and death, much more new loiowledge must be acquired 
and piit to use. It is on the fulfillment of these primary needs that the 
National Heart Institute program is focussed. 

The complexity of the medical problem, as portrayed by the various 
types of heart disease and the fact that these range from the newborn to 
the aged, gives some indication of the scope of the research that must 
be undertaken to obtain essential facts. This research encompasses not 
only the heart and circulatory system, but also interrelated organs and 
systems, the aging process, and hereditary and environmental factors. 

Some of the accomplishments of the research and related programs of 
the National Heart Institute in the past year, as well as some of the 
directions for further progress in 1957, follow. These summarize National 
Heart Institute activities which the appropriations provided by the 
Congress make possible, 

RESEARCH CONDUCTED BY NATIONAL HEART INSTITUTE 

The ultimate goal of the research program carried on at the National 
Heart Institute is the achievement of methods for the prevention and treat- 
ment of diseases of the circulatory system— that is, the heart and ■bl6o5" ^ 
vessels, ^iany aspects of these disorders are still poorly imderstood| in 



- ^ - 

many instances the normal functional mechanisms, of which the diseases 
are impairments or perversion, have not been fully elucidated. The estab- 
lishment of a firm foundation of such fundamental information is the surest 
approach to the eventual solution of the problems of heart disease. At 
the same time opportiinities exist for the improvement of methods for the 
treatment and prevention of heart disease on an empirical basis and deserve 
the fullest exploitation. For these reasons the program of the Heart 
Institute involves a broad approach to the problems of heart disease with 
considerable emphasis on the fundamental biochemistry and physiology con- 
cerned with the function of the circulatory system. The clinical aspects 
of the program provide an opportunity for the early trial of more btisic 
developments while at the same time providing orientation of the more fund- 
amental disciplines toward the problems of heart disease. 

Atherosclerosis 

Atherosclerosis (a form of hardening of the arteries) is the com- 
monest major disease of the cardiovascular system and one of the most 
frequent causes of heart disease and death. It is characterized by an 
irregular thickening of the lining coats of blood vessels that gradually 
encroaches upon their bloodcarrying channels, impairing the blood supply 
to the areas the vessel serves. Not infrequently the thickened vessel 
walls become the site of clot formation or thrombosis which shuts off the 
channel completely and the region supplied by the affected artery is 
deprived completely of its needed oxygen and nutriment. 

The vital arteries most commonly involved in atherosclerosis are 
the coronary arteries which supply the heart muscle itself and the cerebral 
vessels which carry blood to the brain. Involvement of the coronary 
vessels leads to heart attacks (coronary occlusion, coronary thrombosis, 



X !• 



- 5 - 
myocardial infarction) . Involvement of the cerebral arteries leads to 
gradual impairment of brain function or, more suddenly, to strokes. The 
process which underlies atherosclerosis is an acciimulation of fatty 
materials in the lining coats of blood vessels, and it is now rather 
generally accepted that the initial disturbance is to be traced to an 
abnormal handling of fatty substances in the body. 

Because it is believed to be fundamental to the problem of pre- 
venting and treating atherosclerosis, a major and expanding part of the 
Heart Institute program is concerned with the study of mechanisms involved 
in the absorption, distribution and utilization of fat and fatty substances 
in the body. The aim is to determine how these processes operate normally, 
at what points they may become disturbed, and to determine the depart- 
ures from the normal in patients with atherosclerosis and with disorders 
of fat metabolism commonly associated with the rapid development of 
atherosclerosis . 

Just as soaps or detergents are reqtiired to make fatty substances 
soluble in water, special chemical entities are necessary for the transport 
of fat in the watery fluid of the blood. In the blood plasma the fats are 
carried attached, in complex arrangements, to the plasma proteins. The 
attachment of fat to protein does not, in general, occur spontaneously but 
requires the mediation of certain enzyme systems. The operation of these 
systems has been under intensive study and some of their components have 
been clarified by Heart Institute investigators in the last several years. 

One facet of the problem, previously puzzling, is now open to 
solution. It has been known for some time that injection of the anticlot- 
ting drug, heparin, causes the appearance in the circulating blood of an 
enzyme system which can reduce largo fatty aggregates, believed to be 



- 6 - 
directly related to atherosclerosis, to smaller harmless products. It 
has not been known whether the heparin merely causes activation or release 
of the enzyme system or is an integral part of it. Now the development 
in Heart Institute laboratories of a strain of bacteria which specifically 
destroys heparin will make possible a definitive answer to this question. 

Because of the particularly close association of atherosclerosis 
with increased concentrations of cholesterol in the blood, various 
measures aimed at lowering the blood cholesterol content have been tried 
in patients on an empirical basis, (Cholesterol is a particular species 
of lipid or fatty material found universally in animal tissues,) Such 
measures have been the administration of the related plant substance, 
sitosterol; medication with a compound, phenylethylbutyrate, reported in 
the French medical literature to reduce the blood cholesterol; the adminis- 
tration of female sex hormones on the basis that significant atherosclerosis 
develops relatively infrequently in women before the menopause. Although 
none of these trials has proved promising, they are illustrative of the 
approach to the problem at the clinical as well as the fundamental level. 

Hy pertension 

The major approach to the problem of hypertension or high blood 
pressure has been through efforts to develop safe and reliable drugs for 
keeping the blood pressure at normal levels. The many drugs currently in 
use for this purpose all have serioiis limitations of one sort or another, A 
new compovind derived from the seeds of a Panamanian tree is now receiving 
its initial tentative trials in patients with hypertension. It is particu- 
larly interesting because the results in animal experiments indicate a 
unique mechanism of action through an effect on centers in the central 
nervous system concerned with the regulation of blood pres&ure, Xt is too 
early to predict its usefulness in the human disease. 



- 7 - 

Studies with the drug, resorpine, derived from Indian snake root 
and now widely used in the treatment of hypertension and for its "tran- 
quillizing" effects in patients with mental disorders, have opened a new 
and exciting field of drug researdh and at the sarae time have brought 
together two apparently unrelated lines of Heart Institute research. It 
was found that when reserpine was administered it caused the release, 
from various areas in the bodjj of a substance known as serotonin. The 
latter compound had previously been under study because it had been thought 
to play a role in the regulation of the blood pressure through a direct 
effect on blood vessels. It now appears that the effect of reserpine is 
due to its property of causing the release of serotonin, that the pertinent 
effect of serotonin is probably in the central nervous system where it may 
be concerned in the transmission of nerve impulses within the brain centers. 
Particular interest lies in that center concerned with the control of the 
blood pressure. The implications of this finding and its various facets — 
which have pertinence not only to heart problems but to nervous and mental 
function as well — are being extensively explored. 

It is worthy of note that the essential discovery in this area 
and the entire exploration which it is undergoing have been made possible 
by a new analytical instrument, the spectrophotofluorometer, devised in 
Heart Institute laboratories. This instrument makes possible the ident- 
ification and quantitative measurement of minute amounts of a wide variety 
of substances by the characteristics of the light they emit when excited 
with ultraviolet light of particular wave lengths. It has proved inval- 
uable not only for the study noted here but in a number of other unrelated 
problems as well. The notable and unforeseen applications of the instru- 
ment are an excellent example of the way in which fundamental developments 



- B - 
contribute to scientific progress in directions which can not be antic- 
ipated. 

Co nRest iv e Heart Fniliire 

When the hecrt muscle is no longer able to carry the load imposed 
upon it, a characteristic complex of derangements and symptoms ensues 
id.th breathlessness and swelling of the ankles and legs as the most com- 
monly observed features. These sjrmptoms are those of congestive heart 
failure and, in general, are directly attributable to retention in the 
body of excessive amounts of salt and water. Congestive heart failure is 
a result common to many types of heart disease. When properly managed the 
patient who has developed cardiac failure may often look forward to many 
years of useful life. Improvement of our understanding of the disordered 
physiology involved and improvement of methods for managing the heart 
failure patient are therefore highly desirable* 

Studies are in progress to evaluate the various factors which make 
up the workload of the heart muscle and which determine its requirements 
for oxygen and oxidizable foodstuffs. It has been found that the utiliaz- 
tion of oxygen by the heart muscle of the experimental animal is directly 
proportional to the pressure against which the heart must pump the blood 
and to the frequency of the heart beat. Surprisingly, there appears in 
preliminary experiments to be no relationship of oxygen requirements to 
the volume of blood expelled with each beat. If these findings are con- 
firmed in m.ore extensive experiments they may have an important bearing on 
the handling of patients since it is when the demands of heart muscle for 
oxygen exceed supply that angina pectoris results and it is probable that 
the significant workload leading to enlargement of the heart and conges- 
tive failure is that which increases the demand for oxygen. 



- 9 - 

The secretion by the ridrencl gland of excessive cnounts of the 
hormone aldosterone has been shown in previous Heart Institute work to 
be the iimnediate cause of most of the retention of salt and water which 
is the major source of the symptoms in congestive heart failure. Studies 
aimed at determining the normal stimulus for secretion of this hormone 
are continuing and, it is hoped, will provide the key to identification 
of the immediate source of abnormal stimiili in cardiac failure. These 
studies which utilize a specific bioassay method devised by Heart Institute 
investigators have shown that the normal stimuli to secretion are decreased 
interstitial fluid volume and increased concentrations of potassium in the 
blood plasma. Elucidation of the interrelationship of these stimuli and 
the site of their effects are the problems under current study. 

Surgical Approaches 

Studies aimed at the further development and evaluation of new 
diagnostic techniques are continuing. The application of low temperatures 
to surgical approaches tothe interior of the heart has been furthered. 
Considerable effort has been devoted to the problem of artificial heart 
and lung devices for the maintenance of vital circulation during open 
heart surgery. 

Studies of the use of plastics to substitute for blood vessel 
segments and for the possible replacement of damaged valves are being 
pursued. Of particular interest is a procedure and device for the complete 
by-pass of aortic heart valves by rerouting the main course of outflo^^r 
from the heart at the end of the left ventricle opposite from the normal 
egress, through a valve-containing plastic tube directly into the body's 
main arterial trunk (aorta). The flaws in this proced-ure which have led 
to difficulties, in animal experiments have now been virtually eliminated 



- 10 - 
and animals so treated have shown remarkable health and exercise tolerance. 
The procedure may soon be ready for trial in desperate-risk patients ^^^.th 
aortic valve disease, 

A SSISTAMCE FOE COIvJMUNirY PROGRAI^S 

The National Heart Institute through the Heart Disease Control 
Program encourages and stimulates States to establish, maintain and improve 
community programs of heart disease control. Grants-in-aid are made to the 
States by a formula based on the population and economic needs to assist 
them in developing these programs, jl 

States have utilized these fimds in four major areas with varying 
emphasis on any one of these areas depending upon recognition of the needs 
within the State and the capacity of the State in meeting these needs. 
Several of the States are placing major emphasis on the prevention of rheu- 
matic fever and rheuma-tic heart disease. This is being done, for example, 
through supplying prophylactic drugs to those patients with rheumatic fever 
who are unable to secure the drug by other means, through support of diag- 
nostic clinics, and through the use and coordination of other community 
services. Other States have placed major emphasis on raising the level of 
understanding of the cardiovascular diseases by the public and in coopors- 
tion with various professional and voluntary societies in maintaining a 
high level of professional competency. This is being done through supply- 
ing educational materials to the public and by assisting in the sponsor- 
ship of professional seminars, institutes, and conferences. Still other 
States have emphasized the development of community services such as diag- 
nostic clinics, nursing services, and social work services. Finally, a 
few States have been able to devote a considerable portion of their energy 
to various operational and epidemiological research projects for the purpose 



- 11 - 

of better understanding the distribution of the cardiovascular disease in 
the population, the field evaluation of research findings as yet unapplied^ 
and the evaluation of progrsjn techniques now in use, 

Consviltation Service s 

In the development of heart disease control programs, the States 
have encountered numerous problems such as lack of trained personnel, diffi- 
culty in determining the most feasible and profitable direction of program 
development, and technical difficulties in activating programs. Technical 
and professional services are provided to the States to assist them in 
meeting some of these problems. For example, consultation has been furn- 
ished to States in the development of medical social work services, in the 
development of record systems for clinics, and in meeting problems of 
nutrition services. 

The caliber of community services which are provided depend, in 
part, upon the extent to which the latest information is being received 
and utilized. Exhibits, informational material and specialized tradning 
courses are being developed and used to bring about maximum utilization 
of results of research which are now applicable. 

An important function of the Heart Disease Control Program is to 
study and evaluate techniques which will prevent heart disease or minimize 
disability or socio-economic loss resulting therefrom, and to determine 
the magnitude and trends of the heart disease problem for epidemiological 
and program planning purposes. Studies have been undertaken to determine 
the incidence and prevalence of various cardiovascular diseases in differ- 
ent segments of the population in the hope of isolating environmental or 
social factors which might be useful in the development of control measures j 
to determine the value of various tests for use in screening out disease 



- 12 - 
and diagnosing disease j to determine the long term significance of various 
screening test results; and to evaluate rehabilitation procedures, weight 
reduction procedures, and the relationship between nutrition and the devel- 
opment of heart disease In older population groups, 

HEART GRANTS -- RESEAR CH AND TRAH^ING 

Encouraged by the research grant program of the National Heart 
Institute, investigators working in the area of cardiovascular and related 
diseases have been stimulated to increase their research efforts. These 
efforts involve the continued use of proven research methods as v;ell as the 
development of new ideas and new techniques. The inoreasing opportunity 
for the development of new information about cardiovascular disease empha- 
sizes the need for continued research grant assistance to established and 
developing laboratories as well as the need for additional personnel 
skilled in the techniques of modern science and medicine. Through the re- 
search training grant and research fellowship programs of the National 
Heart Institute, selected young scientists are being trained and encouraged 
to join presently productive research teams and to enter yet undereloped 
but. promts log cardiovasnular research areasj through the National Heart 
Institute clinical training grant and traineeship programs, persons are 
being trained to effectively utilize research results in problems of patient 
care and community welfare. Thus, the National Heart Institute research 
and training grant programs provide a means by vjhich new ideas are developed 
and translated into effective weapons in the fight against heart disease. 

Heart Research Grants 

By means of the research grant program, the National Heart Institute 
plans "to oantinue its suppori^ of mer].torLous riindaiiwiii+/il and. cliniosJL Xb- 



.^■i'lOX" £10 J 



- 13 - 

search projects, stimulate research in areas that in the past have not re- 
ceived adequate development, and encourage the application of recently de- 
veloped scientific methods and skills to the prevention, diagnosis, and 
treatment of cardiovascular 6nd related diseases. 

During the past year, several important findings have been uncovered 
and have taken their places in our information about cardiovascular disease. 
A few of these findings are: 

A rteriosclerosis 

Research scientists have long been concerned with the relationship 
between arteriosclerosis, coronary heart disease, and the level of certain 
blood fractions such as cholesterol and proteins. In attempting to deter- 
mine the mechanisms by which the blood level of cholesterol is regulated, 
investigators at the Harold Brunn Institute, Mount Zion Hospital, San 
Francisco, have greatly clarified the role which the liver plays in this 
relationship. At the research laboratories of the I'liarai Heart Institute, 
studies have been conducted to determine the relationship between the 
types and concentrations of protein and cholesterol fractions in the blood 
and their concentration in the walls of blood vessels. Certain unique 
features concerning the blood level of these substances, and their deposi- 
tion in various tissues, as well as the effects of age, diet, and sex, have 
been determined. 

Investigators at the Department of Nutrition and the School of 
Public Health of Harvard University have studied the relationship of body 
musclei mass and energy expenditure as a regulatory factor in the control 
of blood cholesterol levels. These studies have revealed that the blood 
cholesterol levels of Nigerian natives were significantly lower than that 
of a matched group of United States citizens. The. use -of different 



- 14 - 

cultural and genetic groups with different dietary habits, is an important 
approach to the study of cardiovascular disease. These same investigators 
also have undertaken long-term studies to determine the effects of weight 
reduction, caloric intake, and stress on blood cholesterol levels. The 
results of these studies seem to confirm the theory that caloric balance 
plays a major role in controlling serum lipid levels, that elevated 
serum lipid levels contribute to the causation of arteriosclerosis, and 
that weight reduction may be a proper treatment of this disease. 

The effect of environmental and inherited factors on the incidence 
of arteriosclerosis is being studied by research workers in Boston and 
at the University of Minnesota, At the University of Oklahoma detailed 
studies are bfeing conducted on patients with coronary artery disease and on 
normal individuals to determine the effects of emotional development, life 
experience and behavior patterns on blood lipid levels. Scientists at 
Louisiana State University, using newly developed microscopic techniques, 
are engaged in a study of arteriosclerosis occurring in young people in the 
United States and abroad. 

Hypertension 

The effective treatment of high blood pressure is particularly impor- 
tant because this malady not only produces harm in its own right, but often 
complicates and aggravates other diseases, such as coronary heart disease. 
At Duke University investigators are continuing their efforts to evaluate 
the effectiveness of several new anti-hypertensive drugs. These scientists 
have reported that one of these drugs (hexamethonium) seems to be effective, 
in selected cases, by reducing blood pressure and relieving symptoms. These 
pharmacological studies have resulted in new developments in the priuoiples 
of treatment of patients with hypertension. 



- 15 - 

Statistical evidence has been accumulated at Johns Hopkins Uni- 
versity that hypertension and coronary artery disease often run in families. 
These diseases were found to be three and four times as frequent, respec- 
tively, in the siblings of persons affected as among siblings of persons 
without them. 

Investigators at Creighton University in Nebraska have conducted 
studies to clarify the effects of dietary factors, hormonal activity, and 
emotional factors on blood pressure. Several of these studies have re- 
vealed that massive daily doses of ordinary table salt produce a highly 
significant elevation in blood pressure and an increase in body weight. 
When salt was discontinued, blood pressure and body weight fell to low 
levels and then returned to normal. 

Rheumatic Fever 

Rhetmiatic heart disease, the major heart disease of childhood, is 
caused by rheumatic fever. The results of an international cooperative 
study carried out in 13 hospitals and medical centers in the United States, 
Canada, and Great Britain indicate that under the conditions of the study, 
none of the three drugs commonly used in treating acute rheumatic fever 
(ACTH, cortisone, and aspirin) was more effective than the others. Studies 
do indicate, however, that the routine use of penicillin and sulfa drugs 
administered prophylactically may prevent the recurrence of attacks. 

Rheumatic fever usiially does its worst permanent damage to the heart 
valves. Sometimes, however, the valves remain relatively undamaged and, 
instead, the heart muscle is weakened. Evidence presented by researchers 
of Columbia University and Bellevue Hospital emphasizes the importance of 
distinguishing between these two major categories of rheumatic heart disease 
before attempting any surgical correction of the lesions* The study 



- 16 - 
emphasizes the value of certain new diagnostic techniques in differentiat- 
ing these two types of rheumatic heart disease. 

Studies at the University of Utah have served to provide some ration- 
ale for the hormonal therapy of rheumatic fever. This study revealed that 
rheumatic fever, a disease ordinarily considered not to be associated with 
disorders of the endocrine glands, was often associated with abnormal char- 
acteristics in the function of the pituitary and adrenal glands. The dem- 
onstration of relative adrenal underfunction in these patients has impor- 
tant, long-term clinical implications. 

SurgeU 
The surgical treatment of heart valve lesions produced by rheumatic 

fever has been extensively evaluated by scientists in Boston. These inves- 
tigators have reported that 77 percent of the first five hundred patients 
surgically treated for this particular disease were significantly improved; 
this improvement v;as persistent in all but a small number. Long-term eval- 
uations of this nature relevant to the surgical treatment of cardiovascular 
disease serve as a basis for modifying and improving present day therapy. 

Reports from Western Reserve University and the University of 
Minnesota indicate that patients with impaired circulation of the heart 
(coronary artery disease) may be aided by certain heart operations. These 
operative procedures resulted from experience gained from four or five 
thousand experimental operations on coronary blood vessels. These proce- 
dures hevo been performed on approximate Ij'- 200 human patients, and the 
scientists report improvement in SO percent. 

Heart surgery under refrigeration is rapidly becoming almost common- 
place — and with lifesaving results. Many of the modifications of low-tem- 
perature surgery developed at Hahnemann Medical College, Philadelphia, the 



- 17 - 
University of Minnesota and other institutions are now in use throughout 
the country. After extensive experience with this comparatively new method 
of facilitating operations inside the heart, research workers at the Univer- 
sity of Minnesota have cited direct vision as one of the outstanding advaft.* 
tages of this type of procedure. In the clear and open field permitted by 
refrigeration techniques, structural flaws of the heart can more readily 
be examined and corrected by the surgeon. 

Opportunities For Progress 

Research results such as these, the availability of exciting new 
leads, and the development of new research techniques provide a solid basis 
for improving our understanding of the structure, function, and diseases of 
the cardiovascular system. The opportunity is now available through the 
use of precision instruments such as the electron microscope, for detailed 
study of the anatomy and pathology of the heart, blood vessels, and related 
organs. Advances in enzyme chemistry, biophysics, and nutrition provide 
methods by which cells and tissues can be studied and their role in cardio- 
vascvilar and related diseases more clearly ascertained. The experience 
gained in the rapid strides recently made in the drug therapy of essential 
hypertension and the surgical therapy of rheumatic and congenital heart 
diseases provides a chance to pvirsue promising leads for improved patient 
care. 

Cardiovascular epidemiology has advanced to the point where it pre- 
sents the opportunity of learning what effecc the environment has on the 
developmen-': of cr.rdic vascular disease and what effect the patient with 
cardiovascui3.r disoa-.e has on the family and the comm'jnity. Medical genet- 
icists and epidemiologists are considering the problem of why certain groups 
of people differ in their susceptibility to cardiovascular disease and what 



- 18 - 
effect changes in environmentcl factors, such as nutritlan and temperature, 
have on the incidence of these diseases. 

The National Heart Institute research grant program is geared for 
the exploitation of these research developments and for the development of 
new ideas and new techniques needed for the eventual elimination of cardio- 
vascular disease as the nation's major health problem. 

Heart Training Programs 
l) Research fellowships ; 

The research fellowship program on the predoctoral and postdoctoral 
bases provides a method of replenishing and expanding the pool of trained 
research workers in cardiovascular and related areas. Because of the 
nature of modern research, a program of highly specialized training is 
required before a scientist can hope to be an effective, independent inves- 
tigator. By providing training stipends to outstanding young men and women, 
the research fellowship program provides them with an opportunity for con- 
tinuing their studies and entering the cardiovascular research area well 
equipped to face the complexity of modern medical research. 

Vforking in close cooperation with national scientific societies 
such as the American Physiological Society, plans are being made to utilize 
research fellowships for the encouragement of selected college teachers 
and physicians to take additional cardiovascular research training. It is 
anticipated that not only will these college and medical teachers return to 
their institutions better prepared to launch a research program of their 
ovm, but they will act as a stiniulus to their students to consider cardio- 
vascular research as a promising and rewarding career. 

The National Heart Institute research fellowship program thus con- 
tinues to act as an effective stimtilus for the development of needed research 



- 19 - 
workers in the cardiovascular area, 
2 ) Trainin g grants : 

The training grant program provides for the establishment of 
needed research and clinical training programs in the cardiovascular 
and related areas. It assists the research training of competent young 
people in the medical sciences and encourages the training of physicians, 
nurses and other personnel in the interpretation and utilization of the 
latest available clinical information. These objectives are obtained by 
providing training grant funds for the establishment and improvement of 
training facilities in carefully selected institutions and for the pay- 
ment of traineeship awards by the institution. 

The National Heart Institute plans to continue its present effect- 
ive program of undergraduate and graduate training grants, but in an attempt 
to meet important still unmet needs, has organized a plan for the devel- 
opient of research training programs. These training programs fall into 
four categories : 

1) Geographical — The cardiovascular training resources of a com- 
munity (e,g,, several Institutions) will be integrated to provide 
graduate research training on a cooperative Inter-instltutional basis. 

2) Institutional — The miiltl-discepllned cardiovascular training 
rescources of an Institution will be utilized to provide training on 
a cooperative inter-departmental basis, 

3) Laboratory — The special skills present in selected laboratories 
will be utilized to train individuals from other disciplines in problems 
confronting investigators in the cardiovascular area, 

U) Individual — Scientists will be encouraged to participate in the 
activities of clinical cardiovascular departments, providing these 



- 20 - 

investigators v/ith a better background for understanding the problems 

of the pr.tient and the problems of the clinician. 

Through graduate research training grants and predoctoral and post- 
doctoral traineeships and fellowships, the research facilities of a comin\m~ 
ity, institution, and laboratory can be xitllized in the development of inves- 
tigators who can create new approaches and new techniques needed for further 
advances in cardiovascular research and patient care, 

EPIDEMIOLOGICAL APPROACHES 
Epidemiology, the study of the environment and life history of 
organisms, deals with "where a given disease is found, when it thrives, 
where and when it is not found," It includes the collection and arrange- 
ment of facts "into chains of inference which extend more or less beyond 
the bounds of direct observation." Thus, an epidemiological approach is 
used to explore certain relationships in health and in disease which cannot 
be observed directly through such methods as clinical signs or present med- 
ical tests and instruments. 

In the field of herrt disease, studies using this method have in the 
past led to findings of considerable importance for prevention and treat- 
ment. For example, the value is well known of such studies of nutritional 
diseases like beriberi, pellagra, and scurvyj and of infectious diseases 
such as syphilis (which in its former great prevalence led to many thousands 
of cases of syphilitic heart disease). In rheumatic fever, epidemiological 
studies have helped to demonstrate the relationship of streptococcal infec- 
tions to subsequent rheumatic fever. This has led to prevention and 
control measures currently receiving widespread attention, with National 
Heart Institute and American Heart Association cooperation, as a means of 
stopping rheumatic fever and rheumatic heart disease. 



- 2i - 

Of the epidemiology of hardening of the arterios and high blood 
prGSsui'G and their consequences, however, far too little is knovm today. 
The scanty epidemiological nvidenco which does exist is largely based either 
on the study of mortality statistics, which in the investigation of long- 
term diseases like these are often not very revealing, or on clinical studies, 
which have the disadvantage of being based on observations upon people who 
already have the disease. Clearly, what is required is the epidemiological 
study of these diseases based on populations of normal composition including 
both the sick and the well as they are f o\md in the community. 

How Doe s Heart Disease Develop ? 

It is important for the whole nation to know how, where, when, in 
whom, and why heart disease develops! and many other things, such as what 
are the best techniques for finding it in early stages . 

One study aimed at this very significant aspect of the heart disease 
problem is \inderway at Framinghara, Massachusetts. There, in cooperation 
with the town's health department, physicians. State department of health, 
and State medical society, the National Heart Institute is studying this 
average community with the whole-hearted support of several thousand of its 
citizens as volunteer participants. 

Much knowledge of heart disease will be gained from observations in 
this community over a period of time to find out how many people have it, 
what type they have, at what ages it develops, what factors seem to be assoc- 
iated with it, and other matters. 

About two-thirds of the adults in this community between the ages of 
30 and 60 have been given a thorough physical examination to determine 
whether or not they have arteriosclerotic or hypertensive heart disease. 
Persons in the study will be given follow-up examinations every two years 



_ 22 _ 

to accumulate data on how heart disease develops. 

This approach is expected to produce a number of significant results. 
It may provide definite information as to which factors or characteristics 
are present in people who develop heart disease, A by-prodiict of the study 
will bo the accumulation of data on incidence and prevalence. A further 
result v/ill be an appraisal of the value and efficiency of various methods 
and procedures for diagnosing heart disease. 

F urther Disease Tracing Studies 

The problem of finding out facts about heart disease through epidem- 
iology approaches affords a great area of opportunity for research likely 
to be productive of very useful results? it Is receiving increased atten- 
tion through several facets of the National Heart Institute program. 

For example, through the previously mentioned program of technical 
assistance to States there are developing: Studies in rheumatic fever pre- 
vention ncthodolo^; evaluations of the influence of various socioeconomic 
factors in coronary heart disease | and tests of the significa.nce of findings 
of surveys (such as X-ray surveys for tuberculosis) carried out on special 
population groups. Additionally, studies are under discussion with health 
departments in such areas as high blood pressure and congenital heart disease. 

Mention has already been made of this area of opportunity with refer- 
ence to the stimulation and making possible of further heart epidemiological 
research through the National Heart Institute research grants. It is of 
interest to note in some detail an outstanding exajnple of epidemiological 
research recently recommended by the National Advisory Heart Council and 
approved by the Sxirgoon General. The problem of safety of plasma and other 
blood products is vital to national defense, and a well-planned study of the 
problem using epidemiological techniques was developed by a committee of the 



- 23 - 

National Research Coiincil, The study, supported equally by the Public 
Health Servioels Heart Institute, the Department of Defense, and the Federal 
Civil Defense Administration, is a large-scale investigation of the amount 
of hepatitis (jaimdice) resulting from transfusions of blood plasma processed 
in different vfays. Its goal will be to find out which of the methods cur- 
rently being used to process blood plasma is most effective in protecting 
patients from contracting hepatitis after receiving plasma transfusions. 

The study, which will be conducted by researchers of the National 
Research Council, is an attempt to determine the best available way of reduc- 
ing the hepatitis risk. Scientists have recently shown that various methods 
of processing blood plasma can reduce the infectiousness of the hepatitis 
virus considerable, and that a combination of methods may be more effective 
than any one alone. Researchers of the National Microbiological Institute 
played a significant role in this v/ork. 

The new epidemiological investigation may help provide answers to 
defense needs for a safe blood product which can be accumulated and stored 
for use in emergencies, Whether or not one of the present methods of pro- 
cessing plasma is found to be sufficiently effective, the study will have 
worked out and established an evaluation procedure that can be used for 
testing new methods of plasma processing that may be developed in the future. 

International Interest 

As Doctor Paul Dudley White, Executive Director of the National 
Advisory Heart Council and President of the International Society of 
Cardiology, has said, the use of epidemiological methods is a subject of 
international interest and cooperation. Such studies, conducted in various 
countries, can help us to find answers to some of the problems of heart 
disease in the United States, Late last year, I participated in a meeting 



- 2A - 

in Geneva with epidcmiologisls and physicians from the United States, the 
United Kingdom, Sweden, Holland, Japan, Guatemala, Italy, and France, 
Epidemiological studies now under way were intensively reviewed, and oppor- 
tunities for new investigations were defined and recommended. A similar 
group discussion in this country is being sponsored jointly by the National 
Heart Institute and the American Heart Association, 

It seems predictable that the enthusiara and interest for concerted 
and cooperative efforts here and abroad in the field of epidemiological 
studies of heart disease will result in well-planned research projects that 
will have an important bearing on solving some of the many problems that 
have to be resolved in order t o make the most substantial inroads upon our 
leading cause of untimely death. 

Many notable advances have been made in heart research in the past 
few years and, concurrently, public health concern and action has also grown, 
so that the benefits of medical research come to be increasingly applied. 
This has been made possible through a collaboration of interests, of private 
and public agencies working together. National Heart Institute activities, 
conceived and carried out as a program of partnership, constitute a basic 
part of the nationwide effort that has made these achievements. Yet they 
are but forerunners of what legitimately may be expected to come in the 
future. 



OPENING STATEMENT 

by 

Director, National Institute of Mental Health 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1957 ESTIMATE 
for 
"Mental Health Activities, Public Health Service" 



Mr. Chairman and Members of the Committee: 

THE CORE OF THE PROBLEM: NEED FOR PERSONNEL 

As increasing attention is given to meeting the problems of 
mental and •sinotional disorders on all levels, it becomes more and 
more apparent that the critical problem is the drastic shortage of 
trained mental health manpower. You may recall that last year I 
spoke of the shortage of personnel in the Southern region of the 
cour/ory. The need there, as revealed by a recent survey of l6 States, 
is for *4-,260 psychiatrists, or more than five times as many as they 
now have. They need seven times as many clinical psychologists, five 
times as many psychiatric social workers, and more than five times as 
many psychiatric nurses than are now available. Preliminary data 
from a similar survey now being conducted ty the Western Interstate 
Commission for Higher Education in eleven Western States indicate a 
need for more than 2,000 psychiatrists plus an equal number of clini- 
cal psychologists and psychiatric social workers , 

Working toward the increase of trained mental health personnel 
has of course always been an integral part of the program of the 
National Institute of Mental Health. Since the inception of the grants 
program in 19^7; about i+,000 persons have received support for training. 
A great number of the persons whose training was supported with National 



Mental Health Act funds are now engaged as teachers, researchers, and 
heads of clinics, hospitals, and mental health progi^ams. It has been 
our policy, in awarding grants to training centers, to stress the 
selection of trainees interested in public service, teaching, and 
research careers. 
Developing Psychiatric Training 

Training grant funds have been instnunental in developing or 
improving undergraduate departments of psychiatry in the majority of 
medical schools and, at the graduate level, they have helped to improve 
and expand psychiatric teaching of physicians in training centers in 
all parts of the country. In the same way, grants have assisted teach- 
ing centers for psychologists, psychiatric social workers, and psy- 
chiatric nurses. Grants also have been directly responsible for the 
inauguration of mertal health curricula for all student health officers 
in six of the ten schools of public health in the United States. 

During 1956, grants have been awarded to 73 of the 80 schools of 
medicine with k-year curricula, for the pur^.ose of improving, expanding, 
or developir.g p^yehiatric teaching. This means that approximately 
26,000 of the 28,000 medical students enrolled in our medical schools 
are receiving better psychiatric instructior. and training to prepare 
them to deal more effectively with the problems of emotional disorder 
or mental disease encmmtered in general practice. In addition, the 
Institute has sponsored a series of regional conferences in the West 
and in the South for professors of psychiatry in n^edical schools, so 
that they can work toward developing more effective mental health 
educational techniques dui-ing the first t'ro years, the pre-clinical 
years, of medical education. 



- 3 - 

During 1956, 91 grants were awarded to assist graduate training 
in psychiatry, 73 in clinical psychology, U7 in psychiatric social 
work, 28 in psychiatric nursing, and 7 in public health. 
New Horizons in Training 

To help overcome the shortage of teachers in the mental health 
professions, a training grant program has "been established, on the 
recommendation of the National Advisory Mental Health Council, to 
assist in preparing promising individuals for such careers. These 
grantees are nominated by their universities, which assume responsibility 
for providing and supervising the required programs of training and 
experience. In 1956, funds are available for 17 such grants. We hope 
to expand this activity during 1957. 

There is a critical need for professional personnel trained to 
work in special problem areas such as juvenile delinquency, mental 
retardation, mental hospital administration, among others. To help 
meet the need, the Institute has been pioneering new methods. Small 
grants, ranging from four to six thousand dollars each, have supported 
a series of 3 to 5-day conferences on mental retardation in different 
parts of the country, At these conferences, outstanding leaders and 
educators in the field of retardation bring to pediatricians, general 
practitioners, clinical psychologists, and psychiatric social workers 
up-to-date information on causes, diagnosis, and treatment of retarda- 
tion, as well as on management of the retarded and ways of counseling 
parents with retarded children. In addition to bringing new knowledge 
back to their jobs with them, it is expected that the participants in 
these conferences will stimulate further interest in the problems of 
retardation in their home ccmmxuiities. 



At another level, a 5-year grant totalling $113,000 was awarded 
to the George Peabody College for Teachers in Nashville, Tennessee, to 
develop a program of training for clinical psychologists who will work 
with the severely retarded child. Seven outstanding candidates are now 
in training, and the one person who has completed his training is 
Director of Education at a State school for mentally retarded children. 
The Federal grant has stimulated additional support from the State and 
the college. More important, the college has indicated its intention 
to underi/rite the program after the grant from the Institute terminates. 
SUPPORTING AND STIMULATING RESEARCH 

The pronounced increase in public and professional interest in 
research in mental health and disorder over the last decade has paral- 
leled the increase in size and scope of the National Institute of 
Mental Health's research grants program. The 335 research projects 
and several thousands of research workers tl;roughout the country whose 
work has been assisted by Federal funds through this Institute have 
undoubtedly constituted a major stimulant to interest in these fields. 

One important related development has been the provision of 
additional funds from such sources outside the Institute as the Ford 
Foundation and the Foundations* Fund for Research in Psychiatry. As 
a result of the actions taken by the Governors ' Conference during the 
past 2 or 3 years, there has been a tremendous increase in interest in 
support of mental health research in many State programs. The best 
figures now available suggest that the total funds (Federal, State, 
local, and private) available for research in mental health and disease 
have approximately doubled between 1950 and 1955* 



- 5 - 

More Uges for -Research Fxindg 

Another concrete result of the recent stimulation of mental health 
research has been the increase in the number of requests for support. 
The November 1955 meeting of the National Advisory Mental Health Council 
appri^ved k2 applications, only 35 of which could be supported with funds 
allotted to the first half of the fiscal year. On the basis of past 
experience, it is anticipated that, following the February meeting, there 
will be almost $600,000 in approved projects for which no funds will be 
available during the remainder of the fiscal year. This backlog may be 
expected to rise to one and one half million dollars by Jtine of 1957. 

Good research proposals are now coming in from areas of the 
country and institutions not previously represented among the Institute's 
roster of research grantees. We are also beginning to get more applications 
from community mental health resources, from State schools for the men- 
tally retarded, and from local health and welfare departments. 
New Topics 

Another indication of this spread is the number of research appli- 
cations on new topics of research. One such field is psychopharmacology. 
There has been a significant increase in applications on such subjects 
as the effects of drugs on psychiatric patients, the effects of drugs on 
learning, and the use of radioactive tracers to study the metabolism of 
drugs which affect mental processes. For this reason, it has been 
decided to hold a Nationwide conference of scientists this June to con- 
sider the problem of evaluating these drugs and the public health impli- 
cations of their widespread use. 

In addition to the award of grants by the Institute for several 
special studies on mental retardation, there has been an increase in the 
ntunber of projects in this field supported by the research grants program-- 



rlO^ 



- 6 - 

a result of the increased appropriation made for this purpose last year. 
Still another new topic of increasing research interest is the emotional 
impact on patients of a wide variety of diseases. Support is heing pro- 
vided for studies on the role of emotional factors in rheumatoid 
arthritis, the effects of hearing loss on the mentally retarded, and the 
role of psychological factors in asthma, cancer, surgery, and infectioxxs 
diseases. 
New -Developments 

Two important conferences were held during 1955 with support from 
the Institute grants program. One of these, sponsored by the American 
Psychological Association, was a national conference for planning research 
on the psychological aspects of aging. The other, held at the University 
of Wisconsin, was a symposium on interdisciplinary research in the 
behavioral, biological, and biochemical sciences. 
New -Research -Manpower 

The Institute's career investigator program, designed to support 
the work of outstanding young investigators and help them begin research 
careers, is now in its third year. Three career investigators were 
appointed in the first year, an additional 5 were awarded grants in 
1955 > it is anticipated that an even larger number will receive grants 
in 1956. The response to the program has been very favorable, and 
already the award of a career investigator grant is seen as a mark of 
recognition. 

Another source of research manpower is the individuals whose 
training and development have been assisted by research fellowships, 
either predoctoral or postdoctoral, awarded by the Institute. More than 
30 such former fellows have become investigators on regular Institute 
research grants or have joined the Institute's research staff. Many 



r,:--*-: 



- 7 - 

other fellows, of course, are currently engaged in research not supported 
by the Institute, or have become faculty members at universities. As a 
restilt of the increased funds made available this year, it vd.ll be 
possible for us to award approximately 90 fellowships during 195^, as 
compared with hQ in 1955. 
The "Range of -Research 

Among the 210 research projects being supported by grants from the 
Institute as of July 1955 ^ emphasis is being given to such fields as 
clinical psychology and clinical psychiatry, as well as to basic bio- 
chemical and physiological investigations. Studies cover such subjects 
as the psychoses, psychosomatic disorders, evaluation of psychiatric 
therapies, the development of diagnostic instruments, psychoses of the 
aged, and drug addiction. Another area of emphasis is concerned with 
the emotional development and special problems of childhood and adoles- 
cence. Other projects are concerned with such problems as the effect of 
environmental stress on mental health, the effect of the total hospital 
environment on patient recovery, and the relation of brain physiology and 
chemistry to behavior, normal and abnormal. 

Studies supported by the Institute have been partially successful 
in probing the biochemical basis of phenylpyruvic oligophrenia, a form 
of mental retardation. Although this is a rare affliction affecting only 
some 500 cases a year, the project is noteworthy because it indicates the 
possibility of successful treatment for a type of mental deficiency with 
an organic cause for which hitherto it was felt nothing could be done. 
With the knowledge that this deficiency is caused by the body's failure 
to make proper use of one of the amino acids the investigators have 
evidence that, if the condition is detected early enough, dietary treat- 
ment may result in marked improvement. 



- 8 - 

The Institute is also supporting research in which the effect of 
the emotions on the ftmctioning of various internal organs is being 
studied. It has been reliably established that under identical conditions 
of stress, one person's autonomic nervous system may become more liable 
(his heart rate speeds up markedly, his skin resistance drops abruptly, 
etc.) while that of another person may become less so. These distinct 
patterns, which characterize how people's nervous systems react under 
stress, seem to be stable over long periods of time. This finding is of 
great significance, because it now gives us a way to study why some 
people under emotional stress may react by getting ulc«rs, asthma, heart 
symptoms, skin disorders, etc., while others may not display any such 
bodily illnesses. 

NE\; TRENDS IN MENTAL HEALTH RESEARCH 

VJhether mental illness is the restilt of an organic disease of the 
brain or is traceable to the individual's life history and experience 
has been a central question of research in mental illness. These two 
points of view are now being combined into a much more reasonable formu- 
lation than either one represents individually. There is good evidence 
that early childhood experience and abnormal stresses of living are 
factors contributing to or aggravating emotional and mental disorders, 
but only in those individuals susceptible to such disorders. Evidence 
is accumulating that this susceptibility may in some cases be genetic, 
and new techniques and new findings in anatomy, physiology, and bio- 
chemistry are permitting us to develop some of these significant leads. 
Techniques of microcytochemistry permit investigation of the chemical 
structure and metabolism of the brain and its individual components with 



a precision undreamed of a few years ago. Paper chromatography, and 
infrared and ultraviolet spectrophotometry, provide techniques for 
examining the blood and urine for the presence of abnormal substances 
in certain mental diseases. Psychopharmacology has enlarged within 
the past 3 years as an important field devoted to the study of drugs 
which act upon mental state eind mental disease. The relationship 
between some of these drugs such as lysergic acid and normal body con- 
stituents such as serotonin poses a challenging possibility that dis- 
orders in specific types of motabolism may be a significant factor in 
schizophrenia, just as biochemical phenomena are known to cause at 
least one type of mental retardation. 
The -Institute 's Labo ra tory -Rgpearch -Program . 

The National Institute of Mental Health shares in originating 
and encouraging these new research trends. Its own research program 
which has placed great emphasis on physiology, pharmacology, and bio- 
chemistry, in addition to psychology, sociology, and psychiatry, antici- 
pated the most recent developments. Institute scientists are actively 
pursuing the new biochemical techniques, the study of hallucinogenic 
drugs, such as lysergic acid, and the origin of bionhamical approaches 
to therapy. One of its senior scientists is a world authority on the 
process of biological methylations--the mechanism whereby hallucinogenic 
agents are produced. 

A number of highly significant studies are being conducted in the 
Institute's laboratories on the relation of neurophysiological processes 
to behavior. From these studies data are emerging that throw new light 
on the structure and functioning of the brain and central nervous system 
both in normal and diseased states. 



- 10 - 

The - Ins tj-bttt 6*^5- -Clinical Research Program 

The goals of the Institute's clinical investigations program are 
tvo-fold. On the purely clinical side we have selected certain types 
of emotional disorders which constitute serious psychiatric problems; 
"behavior disorders in pre- delinquent children, the schizophrenias, and 
psychosomatic disorders in adults and particularly in children. However, 
we are equally concerned with the prohlems of normal development- -how 
the individual organizes his life experience to form the enduring 
patterns of behavior which comprise what we call personality. We hope 
better to identify and delineate these normal processes by the careful 
study of patients who display certain deviations from the normal. We 
are attempting to integrate psychiatric, psychological, sociological, 
and biological observations in the study and treatment of these patients. 

Studies are now being carried out in the general areas of 
l) methodology of behavioral research, 2) the impact of the social 
situation upon behavioral patterns, 3) contributions to behavior theory, 
h) important factors in normal child development, 5) the nature and 
action of drugs which exert psychological effects, and 6) relationships 
between psychological and physiological processes. 
PROGRAM DEVELOPMENT IN SPECIAL AF,:5AS 

In addition to conducting and supporting r-rograms in all of the 
well-established areas of mental health activity, the Institute has, 
since the passage of the Mental Health Act, developed activities not 
immediately recognized as being highly related to the problems of 
mental health. 



- 11 - 

Problem areas such as the following have been handled: drug 
addiction among minors, rehabilitation of the mentally ill, Juvenile 
delinquency, mental retardation, aging, communication of mental health 
concepts, hospital vs. clinic treatment of the mentally ill, and cultu- 
ral change as it affects the provision of mental health services. No 
one of these areas is totally a problem in the mental health field, but 
each of them presents a challenge to those interested in mental health. 

COMMUNITY SERVICE ACTIVITIES 
The ultimate goal of the Institute's research and training 
activities is to bring to the people who need them the knowledge and 
services that will help maintain mental health and result in more 
effective handling of the problems raised by mental and emotional dis- 
orders. The community services program of the Institute assists the 
States in two ways. Grants are awarded to anable them to develop com- 
munity mental health services, and technical consultation is provided 
to assist in the development of comprehensive mental health programs, 
including coordinated activities both in communities and in mental 
institutions. 

Federal grants have stimulated increased State budgets for mental 
health programs. There was a $3 million increase in State funds for 
such purposes between 195*+ and 1955* and more than a $7 million in- 
crease between 1955 and 1956. The total for 1956 was $25^ million, 
with 37 States showing an increase of 10 percent or jnore over the pre- 
ceding year. 



- 12 



To meet the increased demands for professional consultation and 
technical services from expanded State mental health programs. Congress 
authorized the enlargement of the headquarters and regional office staff 
of the Institute's Community Services Branch. Consultation is provided 
on such varied subjects as the establishment and administration of State 
mental health programs; inservice training; public education; staff 
development; research and evaluation; clinic service; the care, treatment, 
rehabilitation, and follow-up of hospitalized patients; and services for 
handicapped children. The Commimity Services Branch has assisted the 
Sou-:hern Regional Education Board, the Northeast States Government's 
Conference, and the staff of the Western Interstate Commission on Higher 
Education in their surveys of mental health training and research facili- 
ties, and their programs for the establishment of interstate compacts to 
raise the level of existing resources. Consultation was also provided 
in connection with similar programs being developed by a group of Midwesteri 
States . 
Recent Acti-vities 

During this fiscal year, the Institute published in book form a 
report entitled EVALUATION IN MENTAL HEALTH, a review of the problem of 
evaluating mental health services, prepared, with assistance from the 
Institute staff, over a 3-year period by a Subcom littee of the Community 
Services Committee of the National Advisory Mental Health Council. 

The Mental Health Study Center of the Community Services Branch 
is currently involved in several field studies. One is an epidemiological 
investigation of the level of reading skills in a group of ^5,000 school 
children. The study will concentrate on the relatii^nship of reading 



i'.::^'!--:" ' 



J'^; 



- 13 - 

level to early developmental problems, to adjustment in later life, 
and to the presence of any other mental health problems. Another study 
focuses on the post-hospital experiences of mentally ill persons; it is 
hoped that results will facilitate community planning for discharged 
mental patients. 

The Institute is co- sponsoring, with the Office of Vocational 
Rehabilitation, a series of conferences for personnel responsible for 
the vocational rehabilitation of the mentally ill both in hospitals and 
in the community. 
Alcoholism 

During 195^ the Community Services Branch initiated consultation 
services by its regional mental health consultant staff to State alco- 
holism programs, Previously, this consultation had been provided 
centrally by headquarters staff; the new pmcedure will make more 
assistance available to the expanding State alcoholism programs. Other 
recent Institute activities in this field include the sponsoring of two 
national conferences and assistance to research projects. 

BIOMETRICS RESEARCH 

With increased personnel and funds authorized by Congress for 
this fiscal year, the Institute's Biometrics Branch has begun to trans- 
late into concrete studies our philosophy of epiiemiological research. 
Such research can produce important basic data on the incidence and 
prevalence of various types of disorder, as vrell as data needed for 
analysis of the long-term effectiveness of treatment methods. These 
studies will eventually provide us with vital information about the 
natural history of the mental diseases, comparable to data which have 



::;[;■■ 



- Ik - 

been so useful in dealing with the infectious diseases. Already long- ' 
term follow-up studies of patients are raising intriguing and important 
questions which indicate the directions in which future research and 
activities need to be concentrated. 

MENTAL HEALTH STUDY ACT 
Following the enactment of the Mental Health Study Act by Congress 
last year, the American Medical Association, the American Psychiatric 
Association, and 19 other national organizations joined together to form 
a Joint Comiiiiasion on Mental Illness and Health to implement the pro- 
visions of this legislation. The Commission applied to the Institute 
for a grant to conduct the Wation-v;ide analysis and reevaluation of the 
human and economic problems of mental illness provided for in the Act. 
This application was carefully reviewed by a specially appointed review 
committee and was then submitted to the National Mental Health Advisory 
Council with a favorable recommendation from the committee. The Council 
approved the application and the grant was irade to the Joint Commission, 
which will conduct the survey. 

SUMMARY 
Though the need for mental health professional personnel is still 
acute, much progress is being made in meeting this need and in devising 
new and more effective techniques for producing individuals trained to 
work in special problem areas. In the field of mental health research, 
there is increased interest, new and more effective research tools and 
techniques, more fruitful research leads and potentially significant ^ 



- 15 - 

research studies, and an increasing number of scientific personnel to 
carry on investigations. Larger and more active community mental 
health programs are being established, and there is a ferment of 
mental health activity in all parts of the country. The enactment 
of the Mental Health Study Act has resulted in a great upsurge of 
interest in mental health among citizens' groups as well as among 
governmental agencies. A number of the large national civic organi- 
zations, including men's and women's service clubs, are giving heavy 
emphasis to nental health in their programs. The next year or two 
promise greab strides foxTfard for mental health as we begin to reap 
the fruits of past effort and move forward to work out problems that 
are becoming more sharply defined and clearly identified. 



% 



OPENING STATEMENT 
By 
Director, National Microbiological Institute 
Public Health Service 
Presented in Behalf of Gorgas Memorial Laboratory 

coMiyiiTTEE ON approfr:cations 

1957 ESTIMATE 
for 
"Gorgas Memorial Laboratory, Public Health Service" 

Mr. Chairman and Members of the Committee: 

The Gorgas Memorial Laboratory, research agency of the Gorgas Memorial 
Institute of Tropical and Preventive Medicine, was established in Panama in 
1929. Both the Institute and the Laboratory were named for General Gorgas 
in honor of his many contributions to the control of diseases common to 
tropical areas. Since 1929) the United States Government has made an 
annual appropriation to finance the Laboratory's activities. A building 
donated by the Repiiblic of Panama serves as a permanent home for the 
laboratory. 

The program of the Gorgas Memorial Laboratory has been developed 
primarily around the disease problems of the region in which it is located, 
but scientific contributions made by the staff have had application in many 
parts of the world. An example of a current project which is of considerable 
importance to the Continental United States is the research now being 
conducted on jungle yellow fever. Absent from Central America for almost 
a half century, this disease reappeared in Panama in 19^8. Until recent 
years, this form of yellow fever, which is transmitted by tree top 
mosquitoes and maintained in monkeys and perhaps other animals, was not 
believed to be endemic in Central America. The possibility of introducing 
the disease into the United States from distant areas in South America was 
considered remote. Events of the past several years have proved otherwise. 



- 2 - 

Yellow fever has spread northward from Panama into Costa Rica; Nicaragua, 
and Honduras -- in some cases into forests within a few miles of Caribbeaji 
port towns from which either infected persons or mosquitoes might transport 
the virus to the Gxilf ports of the United States . Information on the 
precise conditions which permit maintenance of the disease as it progresses 
toward the United States is urgently needed. 

Scientists of the Gorgas Laboratory have been able to extend their 
studies to include preliminary laboratory experiments on the ability of 
suspected forest mosquitoes in Central America to transmit yellow fever 
virus . Until recently, this work was hampered by the lack of adequate 
insectary facilities for rearing m-osquitoes and maintaining them alive 
during the period when the virus miiltiplies -vrLthin the mosquito. In the 
past year an insectary was constructed and plans made to initiate quantitative 
studies on the biology of Middle American forest mosquitoes. The scientists 
are also considering the possibility that some insect group other than 
mosquitoes may be involved in maintaining the yellow fever virus, 
particularly during the unfavorable dry season. They consider a certain 
species of sandflies as suspect, and in 1957 they plan to test the ability 
of these insects to transmit virus. 

The scientists will also investigate the possible role of certain 
rodents and marsupials in the spread of yellow fever. Experts in this field 
are becoming more and more convinced that the monkey -mosquito cycle of 
transmission does not explain completely the behavior of jangle yellow 
fever. Evidence bearing this out has been uncovered in Brazil and Columbia 
where studies have incriminated certain marsupials and rodents in the spread 
of the disease. 



I 



In other virus studies, Gorgas Laboratory scientists are cooperating 
with scientists of the National Institutes of Health in investigations of 
dengue fever and temperate zone virus encephalitis diseases which are carried 
by mosquitoes. In the latter project; they are testing the hypothesis that 
the real reservoir of encephalitis viruses is in the tropical and subtropical 
regions and that birds may carry the viruses northward during migration. The 
study involves examining human and animal blood specimens for the presence 
of viruses found in the United States and an investigation of Panama 
mosquitoes for presence of virus . 

Toxoplasmosis is a protozoan infection which has been shown to be 
widespread in the human population in the United States and many other 
countries . Its presence has been recognized in Panama, and recently it 
was shown that two primates common to Panama are highly susceptible to 
toxoplasmic infection. Little is known about how this disease is transmitted 
in nature, but insect spread is suspected. Because of the abundance of 
blood-sucking insects in Panama and the availability of sensitive 
experimental animals such as the m.armoset and night monkey, Gorgas Laboratory 
scientists plan to embark on transmission studies of this widespread and 
baffling parasite. 

Research on Chaga's Disease at the Gorgas Laboratory is of interest 
at this time in view of the fact that a proved case of this disease ±a an 
infant was recently reported in the United States. Prior to this, it was 
thought that Chaga's Disease was unknown in this country as a natural 
infection in humans, despite the fact that carriers of the parasite are found 
in the Southwest, and wild rodents and opossums have been found infected in 
that area. 



it 



Recently^ scientists have shovm that the parasite of Chaga's Disease 
can persist in some humans for as long as 20 years without causing apparent 
damage; in others it produces chronic heart disease with an eventual fatal 
outcome. At the Gorgas Laboratory ^ progress has been made in identifying 
the carriers of the disease and devising adequate diagnostic methods- 
Basic knowledge of the host -parasite relationship^ however^ is meager and 
limited largely to the acute fatal disease. No satisfactory treatment drug 
has been found. 

In addition to fostering studies by its resident staff, the Gorgas 
Laboratory also places its research facilities at the disposal of visiting 
scientists. These have included representatives of the Public Health Service; 
the Armed Forces ^ Department of Agriculture, and the Smithsonian Institution. 
Scientists from liniversities and medical schools in the United States and 
elsewhere have also made use of the facilities of the Laboratory as a 
base for carrying out studies on biological, medical and health problems 
in the tropics. Thus, it can be seen that the Gorgas Laboratory exercises 
an influence on tropical research which extends far beyond the work of 
its own staff. 



OPENING STATEMENT. 

By 

Director, National Microbiological Institute 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1957 ESTIMATE 
for 
"Microbiology Activities, Public Health Service" 

Mr. Chairman and Members of the Committee: 

BACKGROUim 

The National Microbiological Institute was established by 
administrative order in 19hQ to conduct and stimulate research in 
the infectious and parasitic diseases, including fundamental 
research on microorganisms as related to public health. Such re- 
search had been carried on at the National Institutes of Health 
(and its predecessor, the Hygienic Laboratory) since 188?, but 
this was the first time it was accorded the status of a separate 
Institute. In 1951, under authority of Public Law 692 of the 8lst 
Congress, the Institute's responsibility was expanded to include 
support of research in establishments outside the Government. A 
clinical program was begun in 1953. 

The 195? budget provides for a substantive increase in the 
subject of allergy, a hitherto neglected area which comes within 
the scientific purview of the Institute. It also allows for more 
realistic support of research in infectious and parasitic diseases 
through a substantial expansion of grants-in-aid. 

GENEliAL MISSION 

Microbiology deals with many organisms, ranging from the 
viruses — the smallest forms having attributes of life--to the para- 
sitic worms, which are large enough to be studied without a microscope. 



m 



- 2 - 

It is concerned with growth requirements, metabolism, and conditions 
of survival of a vast array of disease-producing forms. Equally 
important is the manner in which the infected host (particularly man) 
reacts to the microorganism. The ultimate goals are two: first, to 
prevent and cure the diseases caused by germs and parasites; second, 
to acquire knowledge which will be of use in prevention and cure of 
other diseases. 

THE PROBLEM 0^^ INFECTIOUS DISEASE 

In any study of disabling illnesses, the diseases caused by 
infections rank at or near the top. Among all causes of disability 
the common cold, influenza, and bronchitis are consistently leading 
offenders in every age group. In children, measles, diarrhea, sore 
throat, chickenpox, mumps, and whooping cough are still high on the 
list. In young adults, infections of the throat and tonsils, and 
those of the intestinal tract, are close behind the respiratory 
infections. Even in the middle-aged and older groups, more dis- 
abling illness results from infection than from all other causes. 
In one large industrial organization, 50 per cent of all employee 
absences and 30 per cent of total time lost because of sickness 
were due to respiratory infections. 

Even noxf, we cannot comprehend the real burden of infection. 
As new knowledge becomes available, we have reason to believe that 
all of us suffer innumerable infections which are undetected, or 
misinterpreted. These may be responsible for the appearance of 
illness years later, or even in the offspring of the unknowingly 
infected parent. As long as mankind is afflicted with diseases 



- 3 - 
of unrecognized or obscure causation, the search for hitherto 
unknown microorganisms^ and the intensive study of the effects 
produced by those already knoi/jn, must be pursued with imagination, 
vigor, and advanced methodology, 

THE PROGRAM 0^^ THE INSTITUTE 

All infectious and parasitic diseases, and fundamental problems 
related thereto, fall within the area of general responsibility of the 
National Microbiological Institute. In practice, it is necessary to 
select for attention only a few that can be dealt with. Such selec- 
tion is based upon a number of factors, including: public health 
importance of the disease or problem, need for research, or neglect 
of the particular area, available scientific capabilities, existence 
of leads or likelihood of breakthroughs, enthusiam of the investigator, 
public interest and support. Those problems and research areas which 
are currently receiving special attention, or which represent signifi- 
cant achievements have been chosen for brief presentation in this 
statement. 

The program of the Institute has changed considerably during 
its seven years of existence, and its scientists have been among the 
leaders in the rapid advance of microbiology generallj'', which continues 
at an ever faster rate. 

VIRUS RESEARCH 

Some of the most exciting discoveries in medical science are 
coming from studies on the smallest forms of living matter — the viruses. 
These minute particles may not even be completely living, in the usual 



u 



- h - 

sense, or they may change from non-living stages to those having some 
attributes of life. They produce many diseases — nearly all those 
mentioned earlier in this statement as the leading causes of disability 
are virus diseases. And we are now learning that there is a growing 
number of viruses with which no disease has yet been identified. In 
fa.ct3 there is now under consideration a serious scientific symposium 
on the subject of "Viruses in Search of Disease." 

At the National Microbiological Institute, virologists have 
identified a whole new series of viruses during the past three years, 
which they call the APC viruses (for Adenoidal-Pharyngeal-Conjunc- 
tival) . They originally discovered these viruses in tissue cultures 
made of human adenoids from apparently health children. Then they 
found, after careful study, that some of the viruses of the group pro- 
duced grippe-like illness, and that whole epidemics could be attribut- 
ed to this condition. Virologists, epidemiologists, and clinical 
physicians working together produced the disease in volunteers at a 
Federal prison. Finally, just a few months ago, they made a vaccine 
by killing the virus with formaldehyde, and proved that the vaccine 
prevented infection in a significant number of volunteers. The condi- 
tions designated as "coryza and the common cold" are pre-eminent among 
causes of disabling illness. The APC vaccine is not a common cold 
vaccine, but it will appa.rently prevent cold-like conditions. The 
advance is one of substantial practical and scientific significance. 
The precision with which each step in these studies led to another one 
farther along the road gives sound ground for optimism that further 



- 5 - 

steps will follow. In these studies^ an MMI grantee has collaborated 
with scientists on the Institute's staff c 

This same logical progression has extended the APC virus 
studies into the field of cancer. In the laboratory, these viruses 
grow in tissue cultures derived from human cancer cells. Scientists 
of the National Microbiological Institute and the National Cancer 
Institute have collaborated to study the effects of APC viruses on 
cancer in the human patient. Results bo date are entirely prelimin- 
ary, and have no practical application, but they show that tumor des- 
truction was produced temporarily in 17 cases. These investigations 
are extremely costly, due to the expense of producing and testing 
viruses intended for administration to humans. 

Further studies with the APC viruses are high on our list of 
priorities. And since virologists are nov/ looking at cancer with 
growing boldness, it may bo worth alluding here to an interesting 
speculation. When a virus becomes established in a susceptible cell, 
the basic life processes of that cell are altered in such a way that 
the cell produces new virus material instead of what it should produce, 
When a cell becomes affected by cancer, it produces new cellular 
material instead of normal replacement substance. In each case, some- 
thing causes the cell to alter its mechanisms in the direction of 
abnormal productivity. In the first instance, that inciting some- 
thing is a virus; in the second, it is still unknown. Could there 
be a relationship? 

The "viruses in search of disease" are at present commonly 
called "orphan viruses" by workers in the area. During the past 



- 6 - 
summer, our scientists have made significant contributions to the 
knowledge of how some of these orphan viruses are related to disease. 
Virologists, epidemiologists, and clinicians identified a number of 
illnesses resembling poliomyelitis as being due to certain of these 
interesting viruses, which they isolated and studied. Such polio- 
myelitis-like illnesses are now becoming known as "para-poliomyelitis." 
Our scientists are leaders in relating these causative orphan viruses 
to the group of Coxsackie viruses, in the study of which the National 
Microbiological Institute has made outstanding contributions for 
several years. 

The growing interest in "orphan" and other new viruses has 
reached the proportions of a new concept. This is based upon a 
technique called "unmasking", which permits isolation of viruses 
from cells wuich have grown in an apparently normal fashion for 
weeks or months in tissue cultures. The original isolation of APC 
viruses was an early example of this technique; subsequently many 
hitherto unknown viruses are being unmasked during the course of 
virus-tissue culture studies. It is clearly inferred that the body 
from which such tissues come must harbor unknown viruses for indefin- 
ite periods, perhaps very long ones. New concepts as to the possible 
causation and treatment of poorly understood illnesses are arising 
from these observations, ' 

By another approach, the community study on minor illnesses 
at the Institute's Rocky Mountain Laboratory'', has shovm during the 
year that the APC, Coxsackie, and poliomyelitis viruses tend to pass 
through the population inseasonal waves. One of the significant 



It 



- 7 - 
events which presages such a wave of prevalence is the appearance of 
the particular virus in the sewage of the area. 

IMMUNIZATION AMD Ai'lTIGEN FRAGTIOMTIQN 

An antigen is a substance which stimulates an animal to react 
against it in a certain way. All infectious organisms are antigens 
and hence cause the body to react in a protective manner. We can 
use these organisms to make vaccines by treating them so that they 
continue to stimulate the protective reaction, but lose their disease- 
producing power. At present, vaccines are either microorganisms which 
have been killed or weakened, or certain substances produced by micro- 
organisms. All vaccines contain some material that does not contribute 
to the objective of rendering the host immune, but which can cause 
other reactions. And this is at the root of many of the problems of 
allergic and hypersensitive response which complicates practical use 
of vaccines. 

In the National Microbiological Institute, scientists are 
discovering that only a small part of a microorganism acts as an 
antigen. They are breaking up certain disease-producing organisms 
into fractions, then testing these fractions for antigenic effect. 
Thus far, the studies have involved a virus, a bacterium, and a fungus. 
In each instance, evidence indicates that the outer wall of the indi- 
vidual microorganism contains the antigen. This capsular material has 
been obtained in pure form, and may be clearly seen by means of the 
electron microscope. The cellular contents, xjhich are included in 
all existing vaccines, are apparently completely ineffective in 



- 8 - 
achieving the purpose of immimization. But they are probably the 
cause of many distressing reactions in the injected individual. 

This study contributes to a basic long-range goal in micro- 
biology — the development of better and safer vaccines. We may soon 
reach a stage where the human recipient will no longer be required to 
tolerate painful vaccination and booster injection with such a great 
variety of antigens as we are now offering. This problem will be 
solved if antigen fractionation can be developed to a point of prac- 
tical use. 

Even the long- established and relatively highly successful 
method of immunization against smallpox fails in some instances. 
The wars in Asia have caused this disease to be imported into England, 
France, and the United States. Some outbreaks have been attended by 
high fatality rates. One of the IMI grantees has shown that vaccina- 
tion against smallpox, even with potent vaccine, gives only relative 
protection. Our attempts to reduce the severity of the "take" may 
also reduce the effectiveness of the immunity. This careful study 
throws new light on the distressing problems of vaccination "failures" 
which have concerned military and civil public health authorities in 
recent years* 

HOST RESPONSE TO INFECTION 

Ultimately, it is the host (man) rather than the microorganism 
with which medical microbiology is concei'nedc In tne National Mia-o- 
biological Institute the response of the host to infection is receiving 
increasing attention. 



- 9 - 

At the basic level of the mammalian cell, investigators in 
one of our laboratories have discovered that the building blocks of 
proteins (certain "amino acids") can be pinpointed as being essential 
for growth of selected cells in tissue cultures. An interesting and 
basically significant sidelight is that these cells growing in the 
test tube require a minimum of 12 particular amino acids, whereas the 
whole animal from which they were derived needs only 9. In tissue 
culture, microscopically visible changes were produced when selected 
amino acids were withheld, and the normal appearance was re-establish- 
ed upon supplying the missing materials. The study is currently being 
extended to determine how the requirements of these cells are changed 
when infectious organisms (especially viruses) are introduced into the 
culture. And, indicative of the interest of microbiologists in cancer — 
alluded to previously — is the fact that these investigations are center- 
ing upon cancer cells as well as normal ones. 

At a more complex level, the response of humans to infection is 
being studied in patients who have the curious condition known as 
"agammaglobulinemia." Such individuals have no ability to produce 
antibody, or, in other words, they do not respond to antigens. They 
become infected repeatedly because of this fundamental defect. The 
cause of the condition is unknown though it is intriguing to relate 
it tentatively to a fact previously established by our immunologists, 
namely, that when a pregnant animal is injected with certain antigens, 
her offspring are unable to develop antibodies against those particular 
substances. At the Clinical Center, one such patient has been treated 



- 10 - 
by grafting into her body lymph nodes from a normal sister. This 
has resulted in correction of the defect in the patient with agamma- 
globulinemia. But this may be only a temporary effect, since the 
grafted tissues appear to lose vitality over several months. Never- 
theless, this study is bringing out basic knowledge of host reaction 
to infection. 

New knowledge is coming to light in respect to host reaction 
to certain molds ("pathogenic fungi"). Many of these (e.g., histo- 
plasma, blastomyces, coccidioides, cryptococcus) have hitherto been 
regarded as producers of severe and rather uncommon illnesses. It 
is now becoming apparent that they produce many more infections than 
was previously suspected, and that the majority of these escape diag- 
nosis. Both MIH scientists and grantees are finding these fungi to 
be highly prevalent in the onvironm_ent of some localities; it has been 
surprising to learn how many infections occur, often in epidemic form.. 
It is puzzling that, under some circumstances, few or no infections 
are found in areas where the fungi are abundant. Also, some indivi- 
duals have been able to survive for long periods with very heavy in- 
fections that could be expected to cause rapid death. The field of 
disease-producing fungi is potentially of much greater significance 
in public health than was realized until quite recently. This Insti- 
tute has been in the forefront of research in this area. 

An important segment of this field of host response is that 
of allergy. It has been estimated that 10 per cent of our population 
suffer from major allergies, and an additional ItO or 50 per cent have 






I 



I 



- 11 - 

minor allergic afflictions from time to time. It is hoped that the 
budget increase requested will enable oiar scientists to extend their 
studies into this area of need. 

Intimately related to infection is the phenomenon of immunity — 
the way in which infected animals, including man, react to the challenge 
by the disease-producing organism. One of the reactions to such chal- 
lenge by the infected animal — the host — can be the occurrence of al- 
lergy--which is a heightened or accelerated response to a particular 
type of challenge. IiJhere the host's reaction is of an allergic nature, 
rather th?.n a strictly immunological one, great harm may result, and 
many illnesses arise in this fashion. The science of immunology has 
given us effective vaccines and antiserums, but that branch of it which 
deals with allergy has made practically no progress in a century that 
has been distinguished by almost unbelievable triuraphs over m.any in- 
fectious diseases. 

PARASITIC DISEASES 

The progra.m of the Institute encompasses investigations on a 
variety of diseases caused by protozoans (one-celled animals) and 
worms, with growing attention to related fundamental implications. 
An instance of the latter is the recent discovery of the mechanism 
of action by a compound called pentachlorophenol (PCP). This chemi- 
cal has been under study for several years as a means of destroying 
the snails which are responsible for survival of the worm causing 
a human disease Imown as schistosomiasis. Studies in the laboratory 
have indicated that PGP interferes with certain enzymes inside the 
cell; these enzymes normally transfer phosphates during the process 



- 12 - 
of cellular oxidation. Up till now, this sort of interference with 
a vital cellular process was known to result from another toxic com- 
pound which acted in a different manner from PGP. Thus, this latter 
substance originally studied for a very practical reason, has proved 
to be an intriguing tool for prying into the intimate confines of 
cellular physiology. 

Those studies were done on snails, and led to another interest- 
ing finding that may be of general import. Increased age in the snail 
was marked by decline in the type of enzyme activity which was inhibited 
by the PGP. In other words, age alone seemed to influence a specific 
metabolic process in a manner comparable to that also attributable to 
a particular poison. 

Gratifying advances in studies on toxoplasmosis, a disease 
caused by a one-celled organism, have been recorded during the past 
few yea,rs. The way in which people acquire this disease, and the 
magnitude of its effects, remain undisclosed. Recent studies by MI 
scientists, still in progress, show suggestive differences in occur- 
rence of antibodies against this organism among various groups of 
people. In general population groups in the area studied, incidence 
of antibodies has been about 22 per cent; in persons with illness of 
an unidentified nature, suspected of being possible toxoplasmosis, 
the incidence was 7k per cent. In sera from a group of persons in 
Guatemala, tested for comparison, the incidence of antibodies was 
9ij. per cent. Finally, in a home for mental defectives, one ward 
yielded 52 per cent positives, as against 27 per cent for the whole 
institution. These observations open new avenues for clinical and 



- 13 - 
epidemiological investigation of this poorly-understood infection 
and its significance. 

The parasitologists have extended their studies with germ-free 
guinea pigs. It was previously shown that such animals did not suc- 
cumb to disease when inoculated with amebae which killed the ordinarily 
germ-harboring guinea pigs. More recent work suggests that dead bac- 
teria in the guinea pig's intestine may enable the amebae to produce 
disease even though the animal is free of bacterial infection. It 
may also be possible that dietary changes can support the production 
of disease by amebae in the germ- free guinea pig. 
THE CHALLENGE OF MICROBIOLOGY 

A continuous thread runs through the discussion of the current 
work of this Institute. This thread is the interdependence of science. 
New frontiers for microbiology have been opened by the rapidity of 
adva.nces in the total field of biological and medical research. Funda- 
mentally, the productivity of recent research in protein chemistry 
has opened up the field of tissue culture. The tissue culture technique 
in turn is resulting in an explosive growth in virus research — a growth 
in terms of proliferation of scientific leads as well as in sheer 
volume. Basic cellular physiology and metabolism have made possible 
the development of concepts linking viruses to cancer in ways not 
hitherto conceived of. 

Microbiology, conversely, is contributing to other broad streams 
of science. There is a growing awareness of the potential role of 
viruses as the explanation of some mystifying m.anifestations of cbjronic 



- lu - 

disease. Work on immunology from the microbiological standpoint is 
producing leads useful in tho study of immune and allergic reactions 
in chronic disease. 

In short, as one might have predicted from the way in which 
science evolves, microbiology is in the words of Dr. Vannevar Bush 
"an endless frontier." Microbiology is an area of thu biological 
and medical sciences related not only to diseases for which fairly 
effective protective measures have been found, but an area of re- 
search vital to the total a.dvance of biology and medicine. The 
budget proposed for this Institute is designed to provide the funds 
essential to a productive contribution from microbiology to the total 
advance of medical research. 



OPENING STATSi^EMT 

by 
Director, National Institute of NeiToloi^ical Diseases and Blindness 

Pit) lie Health r.ax-'j Ice 
COMfiLTTEE uN APHi.'PRIATlOlB 
1957 ESTII^iTE 
for 
"Neuroloey and Blindness Activities, Public Health Service" 



I4r, Chairmanj Members of the Committee: 

BACK GROUND 

The National Institute of Neurological Diseases and Blindness budget 
proposal for 1957 is predicated on the many phases of cirrent 
and planned pro?^rai.is and projects in the broad field of neiirological 
and sensory disorders which directly, or collaterally, come within the 
purviev/ of Public Law 692, 8lst Congress, Au^mst, 1950. 

Although the Institute actually was not activated until 1952, 
through the allocation of '1,250,000 within the general appropriation 
"Operating Expenses, National Institutes of Health, Public Health Service, 
1952," the groundwork and development of essential program planning was 
effected and certain aspects of research into the prevention, diagnosis, 
and treatment of neurological diseases and disorders had been initiated 
in 1950. 

Since 195ii, when the National Institute of Neurological Diseases 
and Blindness received its first direct appropriation from the Congress, 
the scope of the program has been increased; clinical and collaborative 
projects have been initiated and coordinated with the program of research 
grants to universities and other non-federal institutions; the training 



- 2 - 

program for scientific and professional personnel has begun to bear fruit j 
and the advances in clinical and siupgical procedures have provided the 
medical profession with new tools. The progress of these past few years 
has been made possible by the increase in annual congressional appropriations 
and by the creation of a more inf orined pvblic opinion of the seriousness 
of neurolop-ical and sensory disorders as a public health problem. 

This crowing public awareness of the public health asjoects of disorders 
is embodied in the creation and growth pf several voluntary health agencies 
dedicated to these conditions, such as United Cerebral Palsy, National 
Epilepsy League, Muscular Dystropl^y Associations of America, National Multiple 
Sclerosis Society, the National Society for Crippled Children and Adults, 
the National Association for Retarded Children and Adults, and the National 
Foundation for Infantile Paralysis. These societies, whose purpose is to 
bring neurological disorders to the attention of the public, have joined 
hands with each other and the American Acadeny of Neurolopy, through the 
National Committee for Research in Neurological Disorders, to formulate a 
national research program in this field in a way consistent with the 
national economy. 

More than 20,000,000 Americans are afflicted by one or more of the 
200 neurological and sensory disorders. They range from cataracts and 
glaucoma to other chronic blinding disorders; from multiple sclerosis 
and muscular dystrophy, to Parkinsonism and apoplexy (strokes); from 
cerebral palsy to deafness and mental retardation of infants and children. 
These disorders represent half of the chairfast and bedridden, and a third 
of all housebound patients in this country, as I testified to you last 
year, the drain on our national resources, both human and material, is too 
sreat a burden to sustain. 



- 3 - 

Today, therefore, I propose to bring you up to date with tl:ie newest 
phases of our research attack on these long term crippling disabilities. 
I propose to attain this end by describing the latest developments and 
needs in our grants programs j by showing you some of the hij^hlic'hts of the 
research progress we have made in the past year; and finally by outlining 
our plans for 1957. 

RESEARCH GFL'INTS 
Since tte first direct appropriation for research grants to this 
Institute in 1952, when : 1,015,000 was made available by the Congress, a 
steady increase in the appropriations has been paralleled by a steady 
increase in the size and scope of the program. The 1955 appropriation 
of !;i3,900,000 served to finance I4O3 projects. With 1956 funds, UlU 
research projects are being supported from an appropriation of ' I;,350iOOO« 
These grants enconpass research activities in 12[i institutions in 38 states 
and the territories of Havjaii and Puerto Rico. 

The urgency of this research grants program can best be evaluated 
by examining briefly the commitments already made. The commitments for 
1957 total 02,889,5it6, for 1958, 5:1,687,770, and for 1959, ^7^2,90?. 
l"Iany of these commitments are on such disease categories as glaucoma, 
cataract, cerebral palsy, multiple sclerosis, muscular dystrophy and 
epilepsy which require an increasing national research effort, 

TRAINING PROGRAMS 

Productive research in the field of neurological and sensory disorders 
depends heavily upon the introduction of new skills and the training of 
clinical teachers and scientists. To meet these needs, this Institute 
provides graduate medical training grants, graduate clinical traineeships, 



- k - 

and research fellowships. As a result of our training grants program, 
medical institvrbions are establishinptj improving,, and expanding programs 
that are pointed directly at the training of teachers and clinical inves- 
tigators in neurology, ophthalmology, and otology. Grants are currently 
being supported in ItO medical schools and hospitals, throughout the country. 

Although this program is only in .its aeoond full year, and is one 
which requires at least five yeara for definitive evalvation, the records 
even now show improvement in training quality, a substantial increase in 
medical school personnel devoted to training, at least ^0% more residents 
in training, and over lOOJ^o increase in the numJjer of medical schools with 
well established training programs in neurology. Already, 26 scientists 
who have received at least part of their training in neurology xmder this 
program have taken teaching positions in other medical schools, 18 of them 
at the instructor level, 7 at the assistant professor level, and one full 
professorship. It is anticipated that practically all of the graduates 
of this program will remain in the new teaching program or will be employed 
to round out the staffs of established programs. There are 80 training 
grants currently being supported by this Institute in the amount of vl>525,000. 

The Graduate Clinical Traineeship Program, also of vital and increas- 
ing importance to this Institute, provides special training in the diagnosis, 
treatment, and care of patients with neurological or sensory disorders for 
neurolocrists, ophthalmologists, and other medical specialists and professional 
personnel who wish to pursue an academic or research career. 

Applications for clinical traineeslrdps have been so numerous in these 
past few years, that only about 10;^ of the most promising; and qualified can- 
didates could be cranted stipends. To date, 8? physicians have completed 



- 5 - 

this specialized trainine. At present, there are awards for 75 trainee- 
ships in the amount of $275jOOO. 

The Research Fellowship Program is directed to youm?; men and women 
who manifest promise and competency for developing careers in neurological 
and sensory disease researcht The effectiveness of this prowam is revealed 
by the fact that over iSfo of those trained have elected to remain in research 
or in teaching. There are hi active research fellowships being sv^)ported 
by 1956 funds in the amount of 1^^150,000. The direct benefit from this 
activity is the provision of a nucleus of trained investigators. The 
significant contributions that these Fellows make to existing scientific 
knowledge is a valuable by-product of the program, 

DEVELOPi^EIff AND PROGRESS 

Already in their short history, the Institute's research and train- 
ing grants programs, together with the research conducted at Bethesda, have 
demonstrated that an effective attack can be mustered and developed against 
neurological and sensory disorders. Specific attainments at this Institute 
or by its errantees show that certain of these disorders can be prevented, 
others can be effectively treated or controlled. Giant strides have been 
made in a few areas which have, heretofore, been considered incurable or 
fatal. 

Permit me to review briefly some of these recent developments and 
advances. 
Fundamental laboratory Studies 

As the Institute's program develops, it becomes more and more evident 
that we must increase our knowledge of the growth, activity, and function 
of the brain and nervous system. The way nerve cells transmit energy, the 



- 5 - 
chemical structure and metabolism of nerve tissue, the metabolism of energy 
in the brain, the areas of the brain which are responsible for the diverse 
types of motor and sensoiy activity -- these are specific basic areas, 
where we are constantly addin'' knowledge — badly needed knowledge for 
specific attacks of c-reater depth on neurological and sansory disorders. 
Progress 

Present studies have provided increased knowledge ofs 

1. Metabolism of nerve cells 

2. Brain chemistry 

3. Basis of nerve regeneration 

h> Pharnacology of nervous tissue through 
the use of radioisotopes 

In many other areas, we are forging ahead to clearer knowledge 
of the basic mechanisms underlying long term neuroloe-ical and sensory 
disorders. 
Eye Research 

The seriousness of eye disorders has been recop-nized, and recently 
the Institute has achieved great progress in the prevention and treatment 
of specific diseases. But, this progress has presented new challenges 
due to propress made in other medical fields. More premature babies survive 
due to advanced obstetrical practices, but the incidence of blindness in 
prematures has movinted at an alarming rate. The increase in average popu- 
lation age has also increased the incidence of glaucoma and cataract. An 
estimated 2,000,000 diabetics, whose lives have been prolonged by various 
new treatments, now run the risk of becoming blind with diabetic retinopathy. 

The challenge of blindness in premature babies, due to retrolental 
fibroplasia has been met. The collaborative project, which provided a rapid, 
precise evaluation on the role of oxygen in the cause of the disease, has 



- 7 - 
cleared the way for its prevention. The findings iiave become routine pro- 
cedure by pediatricians, obstetricians, and hospitals on a national scale. 
The investment of '')5l,000, of Xirhich the federal government contributed 
■UiO,000, has already provided normal eye sight to several thousand children 
who X'joiold have been doomed to a life span of blindness. 

Uveitis, another blinding disease, which is caused by tuberculosis, 
syphilis, and brucellosis, is still under study. It has been proven that 
toxoplasmosis infection does occur in advilts. Therapy with pyrimethamine 
and sulfadiazine indicates that in some instances these drugs are a cure. 
It has also provided control of this supposedly incurable infection. 
Present studies include those with other new drugs that may prove to be 
less toxic to the body. 

This Institute is continuing the study of the use of diamox and 
other therapeutics in elaucoma, which blinds many thousands of people 
annually. Original findings that diamox would reduce the pressvire of 
intraocular fluid, in acute glaucoma enough to permit surgery imre evaluated 
and recent findings proved this drug also inhibited the formation of 
intraocular flviid. 

The cause of cataract has been under study by Institute inves- 
tigators. Experimental cataracts produced in animals by administration 
of the compovind alloxan, has provided knowledge on each stage of forma- 
tion, and development of cataracts. Investigative studies on the biochemical 
and cytological aspects include radiation, metabolic and deficiency cataracts. 

Other studies ef the eye include those on degenerative lesions of 
the optic pathways. Radioactive indicators (isotopes) and autoradio- 
graphic techniques are being used in studies of orbital tumors. The effect 
of corticosteroids on inflammatory diseases of the eye is under investigation. 



- 8 - 
A viral disease - adenoidal-pharyngeal-conjunctivitis - is being studied 
in cooperation witn the National Mcrobiolo<?ical Institute. 

Usini? electronic techniques similar to those developed for television, 
a pupillooraphic machine, which may prove to be a diagnostic tool of value 
equal to the X-ray, has been developed which measures and records the 
subtle chanq;es in size of the pupil of the eye which are invisible under 
direct observation by an ophthalmologist. It provides a means for early 
diagnosis of encephalitis, multiple sclerosis and other neurological dis- 
orders, and offers an accurate method for rapidly testing- medications that 
show promise in halting the progress of neurolo'^isal disease. 

Last year I reported to this committee that the eye research program 
was functioning only on a standby basis due to lack of personnel and 
facilities. The special appropriation of S250,000 to open a nursing unit 
in eye research at the Clinical Center has provided for most of this 
requirement. I am happy to tell you now that this program is in f\jll 
swing and is indicative of continuing achievement. 

Many of the studies are under tine direction of Dr. Ludwig von Sallmann, 
one of the world's most eminent ophthalmologists. Sinse coming to the 
National Institute of Neurological Diseases and Blindness in August, 1955, 
he has developed many of the new approaches and techniques just stated. 
His brilliant achievements, which earned him the Proctor Medal Award in 
195lj are being expanded at the Institute, and his present studies on the 
central nervous control of the intraocular pressure, and investigations with 
autonomic drups to establish the influence of changes occxoring elsewhere 
in the body on the intraocular pressure which offer new approaches to the 
study of glaijcoma, are expected to provide essential leads to the diagnosis 
and treatment of blinding diseases. 



- 9 - 
Cerebral Palsy 

Cerebral palsy covers a wide variety of disca'ders of the brain 
and central rervous system which result in svich conditions as paralysis, 
postviral abnoriTialities, bizarre involuntary movements, speech defects, 
and often mental retardation. It is generally believed that brain damage 
or disease during prenatal development, at birth, or shortly after birth 
is responsible for these neurological deficits. Defined broadly, cerebral 
palsy affects | million children and 2| million adults in the United States. 

The National Institute of Neurological Diseases and Blindness is 
conducting a collaborative research project on cerebral palsy, A compre- 
hensive attack on the cerebral palsies requires a precise pathophysiological 
classification of its various clinical forms. This classification may lead 
to its prevention or successful treatment. A long-term, longitudinal study 
of cases, conducted with the assistance of local hospitals and collaborating 
institutions, has been initiated. Such a project is essential to the under- 
standing of this disorder because of the complexity of its manifestations, 
and the necessity of obtaining a large amount and variety of clinical 
and pathological material for study. Such a stuly requires the cooperation 
of many neuropathologists, obstetricians, and pediatricians. In addition, 
the most effective and well integrated clinico-pathologic correlations can 
best be made by a central laboratory. This Institute is providing the 
services of the central liiboratory and is coordinating the entire stvdy, 
A protocol, developed by scientists representing various fields of medical 
research, includes requirements for information on family and the mother's 
history^ record of events at birthj clinical history and record of clinical 
examinations) a complete record of pathological examinations. This protocol 



- 10 - 
is now being subjected to practical tests in the clinic and concurrently, 
several institutions are completing their plans far collaboration in the 
study. 

The collaborative study of clinic opathologic correlations in 
cerebral palsy will develop into f vll-scale operation with the addition 
of other institutions to the program. One of the first projects to 
pet under way will be an intensive study of the prenatal, natal, and 
neonatal factors producing this crippling disease. 

The Institute also is conducting a study on the physiological and 
anatomical mechanisms which form the substrata of chore oat he tosis, a 
type of cerebral palsy in which uncontrollable and incapacitating abnormal 
movements predominate. Surgical procedixes are being devised and tested 
for sympbtomatic relief in these cases. Studies are being made on the 
effectiveness of new drugs which may reduce the muscle tone and involun- 
tary movements in children with cerebral palsy. Further investigations of 
kernicterus as a cause of cerebral palsy are being conducted. Studies of 
the brains of cerebral palsied patients by means of the pneumoencephalo graph 
have been initiated. 
Mental Retardation 

Mental retardation, which had been a step child of scientists and 
educators for hundreds of years, finally has been recognized as a research 
problem, deserving high priority. Increasing public interest through 
parent groups and other interested organizations gave new stimulus to 
scientists and educators to develop a comprehensive program for research 
and rehabilitation of this tragic condition. 

The total cases of mentally retarded in the United States may be 
up to Ii, 500, 000 of which an estimated 1,500,000 are children. With respect 



i 



w 11 - 

to the mentally retarded children, figures range from l|- to 5 percent of 
the children up to 18 years, with an estimated 3 percent being the generally 
accepted fisvire. Five to ten percent of the mentally retarded are institu- 
tionalized. The estimated cost to the community is C>50,000 per individual 
for the lifetime of the severely retarded who are institutionalized. 

This Committee and the Congress, reco.onizing the tremendous need in 
this area, instituted a government sponsored program in 1956 with an 
appropriation to the National Institutes of Health for research and 
trainin-^ in the amount of 0750,000, Of the funds appropriated to the 
National Institutes of Health, ;:i;500,000 was allocated to the National Insti- 
tute of Neurological Diseases and Blindness, 

The program of this Institute in mental retardation, both at Bethesda 
and through grantees, is designed to strike at the biological basis of the 
various forms of mental retardation with the ultimate aims of its preven- 
tion by eradication of its causes or its amelioration by the discovery of 
new methods for improving brain activity and metabolism. 

Productive research in a diverse problem such as mental retardation, 
where many causes can precipitate the condition and where scientists from 
many disciplines are needed, depends on collaborative longitudinal study. 
This requires coordination of the work of several institutions and several 
scientific disciplines in a master plan devised to track down the most 
promising- scientific leads in this field. The National Institute of Neuro- 
lopical Diseases and Blindness proposes to serve as a focal point for this 
type of collaborative propram shaped to investi ate how brain damage 
sustained before, dijring, or shortly after birth leads, as it so often 
does, to mental retardation — and what methods can be devised to prevent 



I 



- 12 - 
this brain damape or, once it has occurred, how to aneliorate it. This 
program, therefore, calls for a central plan to coordinate the investi- 
gations of obstetricians, pediatricians, neurologists, psychiatrists, 
and other medical specialists as well as investigations from several basic 
neurological and psychological disciplines. 

Before such a program can be launched, however, it is essential to 
assess accurately what is already knoxra in this field, what research is 
being conducted throu.gl'iout the covmtry, and where promising research 
potential lies. To reach this ?oal, the Institute is sponsoring a project 
under Dr. Richard L. Masland, "-^Professor of Neurology at the Bowman Gray 
Medical School, who is making an extensive survey of current research and 
research potential in many departments of many medical schools and institutes 
throughout the country. The results of the f-iasland Project will supply- 
important groundwork for the collaborative longitudinal study which is now 
being planned. 

Another important segment in the Institute's total program in mental 
retardation is being devoted to the experimental production of brain damage 
in unborn or newly born animals resulting in mental retardation. These 
experiraents provide a proving -^round for the identification of anatomical 
and pathological lesions thus acquired in animal brains which should 
supply information which can be applied to ns.n. Scientists at Bethesda 
have completed studies of this nature on guinea pigs and are ready to 



■^'"The Masland project is 'an.der the joint sponsoreaip of tlia National 
Association of Retarded Children, the National Institute of Mental Health, 
and the National Institute of Neurological Diseases and Blindness. 



i 



- 13 - 

apply their newly developed techniques to monkeys along similar lines. 
Institute "rantees are studying congenital malformations of the brains 
of animals, which are produced by X-ray at critical stages of fetal 
developraent. These malformations may result in mental retardation, 
cerebral palsy, or both when the offspring survive. 

Paralleling this step-up in mental retardation programming 
has been an increase in research grant applications, related directly 
or indirectly, to this field. Currently the Institute is supporting 
21 projects in the amount of (310,322, Unpaid recommended research 
grants amount to v7l4,OU7» 
Multiple Sclerosis and other DemyRlinating Diseases 

Multiple sclerosis and other deirryelinating diseases are human 
scourges which attack the spinal cord and brain. These disorders are 
called demyelinating disorders because their common pathological process 
involves the destruction or qrouth arrest of the myelin sheath (a fatty 
substance) which insulates and protects the nerve fiber tracts in the 
central nervous system (spinal cord and brain). 

The Institute pro'-raiTi in multiple sclerosis is a growing, dynamic, 
and coordinated one. Tiine does not permit me to describe all its 
promising developments and accomplishments. 

Let me say at this time, however, that it comprises a tliree-pronged 
attack on this long term crippling disorder, designed to l) uncover the 
cause or causes of the disorder, which are still unlcnam; 2) discover the 
underlying pathophysiological mechanisms taking place in the central nervous 
system; and 3) empirically attempt tlirough trial medications to arrest the 



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disorder from pro?;ressing, even before the causes and underlying mechanisms 
are fully understood. 

Streamlined research now is advancing simultaneously on all these 
fronts. Institute or institute supported investigations are still probing 
possible infections, allergic, nutritional, and metabolic origirs for 
multiple sclerosis and other demyelinating disorders. Information to date, 
while not definitive, favors allergic or metabolic factors as the most 
likely causes of multiple sclerosis. 

Regardin?? oxsr knorJledge about the underlying mechanisms of des- 
truction or failure in synthesis of myelin, substantial progress is being 
made, even though definitive conclusions still cannot be drawn. We are 
learning m.ore and more about the chemical structure of iryelin and about 
the chemical and physical forces that preserve its gra^rth and existence, 
A major break-through in this area occurred with discovery by a grantee at 
Harvard University, vmo by using the electron microscope revealed that the 
nyelin sheath of peripheral nerves developed as the result of a spiralling 
of the membranes of certain satellite cells around the nerve, knoim as 
Schwann cells. 

A precisely similar situation obviously does not obtain for the 
formation of ra^^elin around the r^rve fiber tracts of the spinal cord and 
brain, which are affected in mioltiple sclerosis, because these nerve 
fibers are not surrounded by Schwann cells. However, recent investigations 
by means of tissue culture studies (growth of nerve tissue in culture) and 
the use of the electron microscope indicate that certain satellite cells of 
the central nervous system, known as neuroglia, which may be the counter- 
parts in the central nervous system of the Schwann cells in the peripheral 



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nervous system, probably play an important role in the formation and sustenance 
of the nyelin sheath svirro\3Jiding tte fiber tracts of the spinal cord and 
brain. So important is this development, the Institute has arranged for 
an international conference on neuroglia, to be attended by the world's 
loa'.'Mn-- authorities, this comin'7' March, in order to devise a plan for 
e^.ploitinc thesci possibilities in the most rapid and effective way. 

Wnile these promising breakthrouo'hs in oiat basic knowledge are 
occurring, the Institute also is running clinical trials of medications 
xjhich appear to have promise for arresting the progress of multiple sclerosis 
until a fuller understanding of its causality end its basic mechanisms is 
gair^d and a rational method of treatment or prevention can be developed. 
These clirdcal trials are justifiable inasmuch as multiple sclerosis is 
such a crip.ling disease and covers such a long term in the patient's 
life that almost any promising clinical leads vjhich have been uncovered 
scientifically should be tested. For example, in 19Sh, there were optimistic 
reports of a study made in New York on the effects of isoniazid on patients 
having multiple sclerosis. The Institute, in its Bethesda program, has 
just coirrpleted a study of the use of this iTEdication on 32 patients with 
multiple sclerosis, usin": strict diagnostic criteria and th2 "double 
blind" technique. After three months of testing, it was decided that 
isoniazid did not shoi^j sufficient promise in the arrest of the symptoms 
of multiple sclerosis to be continued any longer.""' The Institute's 



•"•After tlie Institute's program was be'Tun, the Veterans Administration, 
using essentially the same criteria and techniques, undertook a study of 
the effects of isoniazid on about 100 patients with multiple sclerosis in 
30 VA Hospitals, Their preliminary results should be reported at an early 
date. 



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isoniaaid project, thou* disappointinp: in its result, is ndt without 
value for it c;ave an opportunity to our clinical scientists to establish 
definitive diamostic criteria and a controlled methodology in a disorder 
in which clinical progress is most difficult to evalvate. 
i''a: ?cular Dystro p hy and Neuromuscular Disorders 

A broad attack on muscular dystrophy and neuromuscular disorders, 
which by themselves constitute a serious public heeCLth problera, is being 
expanded. Because of the extremely limited knowledfje of these disorders, 
the Institute research program in this field encompasses the creation, 
develop/iient, and use of newer techniques in biophysics, biochemistry, 
and pharmacology. New equipment for studyin'T ne~ijr orauscular electronics 
has been desif^ned, and constructed by Institute scientists, and experiments 
in the application of radioisotopes and other biophysical agents and instru- 
ments have reached an advanced stage. 

Frequently, when medical research is focused on a broad, uncharted 
field, such as muscular dystrophy, ne^rative f indinfrs must precede positive 
findings. Accompaniments or results of a disease process have to be 
elucidated before its cause can be isolated. Such is the present status 
of research in musciilar dystrophy and neurorai;iscular disorders. Institute 
scientists at Bethesda have discovered many important new facts about 
muscvilar dystrophy and have proved that they are not the cause of the 
disorder but a result of the disease process itself. These facts, however, 
are essential building blocks for the eventual determinations of the funda- 
mental basis for ttese disorders and the development of effective preven- 
tatives and treatment. 



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Thus, Institute scientists have discovered that an abncrmal amount 
of sodium is retained witha.n the muscle fibers while potassium leaks out, 
resulting? in an abnormal ratio of sodium to potassium in the muscles of 
patients vjith muscular dystrophy. Moreover, in studies with radioisotopes 
the saiie scientists found that the blood content of the dystrophic muscle 
(muscle biopsied from patients with muscular dystrophy) is the same as 
that of normal muscle. These findings show that neither low potassium 
nor abnormal blood supply is a cause of muscular dystrophy. In another 
series of investigations at Bethesda the excretion of abnoriially large 
amounts of a sugar called ribose in the urine of patients with muscular 
dystrophy vras demonstrated. Here, also, It was proved that the abnormal 
sugar metabolism was an accompaniment, but not the cause of the condition. 

These rewarding projects in muscular dystrophy led Institute 
scientists to an investigation of disorders of the nerve-muscle junction, 
or the place where the nerve becomes imbedded in the muscle, i^yasthenia 
o-ravis is the most comi-ion disorder due entirely to a block in the passage 
of the nerve impvilse from the nerve to the muscle at the nerve-muscle 
junction, which results in paralysis and sometimes death. It is "generally 
believed that niyasthenia gravis is due to the presence of a curare-like 
substance floating freely in the blood, iihich causes a physical-cheiTiical 
imbalance at the nerve-muscle junction, thus blocking the passage of the 
nerve impulse. Cut" are is a substance formerly used to poison arrowheads 
in juncfle warfare. In 1937, it xiias discovered that neostigmine could be 
used as an antidote to curare and curare-like substances, and since that 
time it has been the most common form of treatment for ii^rastisnia gravis. 



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Institute scientists at Bethesda, however, have developed an hypothesis 
ttet passa'^e of the nerve impulse at the neuromuscular junction may be blocked 
by an entirely different substance, called "decamethonivmi", in a way 
(depolarization block) different from that of curare which acts as a com- 
peiition blnr>i<. The chemical antagonist of decamethonium is hexamethonium, 
and recent evidence at the Institute indicates that this latter substance 
may provide a treatment for iTQrasthenia pravis in cases where neostigmine 
has failed. This possibility is no^^r being assessed in patients with 
rr^rasthenia pravis under tlie Institute program at Bethesda. 

Studies on the neuromuscular junction have a wider implication 
than providing new treatments for myasthenia gravis. For it is the 
blockinp- of the passage of the nerve impulse at this jimction, which forms 
the basis of the chemical action of nerve war gases, an antidote for which 
is being xjorked out by one of the Institute's grantees. 
Epilepsy 

Epilepsy is not a disease - but a manifestation of abnormally dis- 
charging brain cells. Apparent only at the time of a seizure, it is a 
transient condition that results in long-term handicaps to often other- 
T^ise normal individuals. Only a small percentage of epileptics with 
extensive brain damage are mentally retarded or affected in mental function,. 
More than a million people in the United States are afflicted, and few of 
these can look forward to a normal life adjustment. It is a problem that 
cuts into every segment of our social structure, and is found in every 

community. 

« 
A greater and continvdng effort must be exerted upon the underlying 

causes and basic mechanisms which give rise to epilepsy in order to (l) 

effect a broader modicum of control of epileptic seizures, and (2) provides 



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a more informed public opinion so that the afflicted will not be deprived 
of normal interpersonal relations and opportunities to obtain or retain 
gainful employment because of the social stigma which has attached itself 
to this disorder. 

Dur.ing the last decade tremendous progress has been made in the 
scientific understanding of epileptic seizures and their control through 
medical and surgical procedures - a movement in which the National Insti- 
tute of Neuroloi?ical Diseases and Blindness 1ms been a major contributor. 
For example, surgical studies at the Institute have demonstrated that 
surgical intervention in patients suffering frora focal epileptic seizures 
(seizures which arise as a result of abnormally dischirging cells from a 
localized portion of tlie brain) benefits most effectively $0 percent of 
the patients undero-ointr such an operation and '=rives partial relief from 
seizures to another 25 percent. 

These surgical studies also provide scientists i-ath the unique 
opportunity of undertaking chemical studies on living brain cells in the 
portions of the brain removed from these patients. Usini?: this approach, 
Institute investigators were the first to reveal a chemical deficit in the 
brain tissue of epileptics as compared to the brain tissue of normal individu- 
als. It was discovered that one important chemical to brain tissue ( plutamic 
acid) does not form in sufficient quantity in the brain cells of epileptics, 
and another chemical (acetylcholine) does not form in sufficient quantity 
in reserve. Institute scientists also discovered that this chemical deficit 
in some instances could be corrected by the administration of two substances, 
^lutamine and asparagine. 



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As a result of these discoveries, this Committee and the Congress 
appropriated $7^0,000 in June, 195U, for extensive cliniDal tests on the 
efficacy of ■:'lutamine and asparagine in the control of epileptic seizures. 

These compounds were purchased in amounts which allowed for expansion 
of the study at the Clinical Center and for the award of grants for similar 
studies at 5 medical schools. The evaluation of asparagine as an anti- 
seizure biological shows that asparagine is reasonably safe as an anticon- 
vulsant which can be administered intravenously or orally. About 60 percent 
of the 150 patients have shown moderate to excellent results. It is 
anticipated that, within the year, a practical method for this test and a 
schedule of dosa.<5;e xjith medication can be established. 

Summary of results - Already, tte research in glutamic acid has stimulated 
the production of synthetic plutamine at a cost of one-twentieth of that 
of the natural compound. A dramatic by-product of the glutamine project 
was the availability of this drug as a basic ineredient of the nei^est and 
most effective polio vaccine. 

PLANS FOR FISCAL YE/\R 1957 

This statement of facts highlights the s ignif icance of the problem 
and some of the accomplisliments of the National Institute of Neurological 
Diseases and Blindness this past year. They also provide a perspective 
of the future objectives of its research program. 

For 1957> the Institute proposes to continve to conduct and 
support lines of research, which as a result of progress in the last two 
years appear to be fruitful. Under these guidelines, the Institute hopes 



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to reinforce its ovrn research and that of its crantees working in the 
basic laboratories of the neurological sciences, particularly neuro- 
chemistry, neurophysiology, and neuropharmacology. Recent advances in 
these disciplines indicate considerable progress may be made in the 
near futut'e. The final results will be applicable to the prevention and 
treatment of svch disorders as cerebral palsy, epilepsy, multiple sclerosis, 
muscular dystrophy, and inany of the blinding diseases. 

The successful production of disease in experimental animals is 
often an essential precursor for later applications to man. In neuro- 
loeical and sensory disorders, this has always heea a difficult task, 
owing to the complexity of the human brain, as compared to that of most 
animals. Recently, however. Institute scientists at Bethesda, and else- 
where, have succeeded in producing experimental cerebral palsy, epilepsy, 
mental retardation, and Parkinsonism, The avenues of research that these 
experiments provide will be pursued to the limit during 1957. 

In addition, the Institute will continue li.ts promising pioneer 
work in brain surgery; chemistry of epilepsy? thf metabolism of muscular 
dystrophy; and the si'-nificance of blocking af^en's at the nerve-muscle 
junction, which is now beinp tested on patients with .riyasthenia -ravis. 
It is also our hope to explore more fully new developments on tlie aftermaths 
of reproductive failures, xirhich most commonly are cerebral palsy and 
mental retardation. 

In the area of blinding and other sensory diseases, the unique 
achievements of the past year or so are also vital factors in the Insti- 
tute's planned perspective for the coming fiscal year. The program for 
this cominfi- year, based on preliminary and interim reports, shows promising 
leads for the future. 



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In the field of training the Institute also proposes to continue 
and strem^then its rewarding programs designed to increase the numbers 
of qualified clinical teachers, scientists, and professional personnel, 
who wish to pursue an academic or research career in neurological or 
sensory disorders. The success of these training programs already has 
been described. 

A spontaneously ^rowing research frontier at the National Insti- 
tute of Neurological Diseases and Blindness has been the organization 
of collaborative research projects, wherein the Institute serves as a 
coordinating axiS; or central focal point, for projects requiring 
collaboration from many hospitals and scientific disciplines. The Insti- 
tute's recent projects in retrolental fibroplasia; in the use of glutamine 
and asparagine for epileptic seizures; and the epidemiological studies of 
amyotrophic lateral sclerosis on Guam, testify to the fruitfulness of such 
collaborative projects, if quick answers are to bo obtained for public 
health problems, which reqviire long term, longitudinal studies. At 
present the National Institute of Neurological Diseases and Blindness 
is the only institution in the United States possessing adequate facilities 
in the field of neurological and sensory disorders to function as a national 
coordinating center for the organization of such collaborative projects, 
which are multidisciplinary and multi-institutional in design. 

New opportunities are developing, and will further develop, for 
the promulgation and formulation of collaborative projects reqi±ring a 
multi-institutional and multidisciplinary approach. The developing double 
tripartite collaborative program (clinical, pathologic, experimental) in 
cerebral palsy; the less developed projects in mental retardation, cerebral 



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vascular disease, and trachoma; and the projected conferences on the neuroglia, 
and temporal lobe epilepsy are examples in point. In essence, these projects 
are collaborative field investiffations and/ or demonstrations in which the 
National Institute of Meurolor!;ical Diseases and Blindness serves as a 
coox''dinatino- axis or central focal point. 

Therefore, as the National Institute of Neurological Diseases and 
Blindness Krovjs it is increasingly necessary that support be given to these 
activities dealing vrith resear'ch requiring collaborative field investiga- 
tions and exploratory demonstrations. These activities, which I propose 
to support by making an appropriate allocation of research grant funds, 
will be reviewed and passed upon by our National Advisory Neurological 
Diseases and Blindness Council, 



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